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Nance MG, Sullivan KM, Puglia MH. The impact of the early environment on oxytocin receptor epigenetics and potential therapeutic implications. Pediatr Res 2024:10.1038/s41390-024-03563-z. [PMID: 39548294 DOI: 10.1038/s41390-024-03563-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 07/26/2024] [Accepted: 08/14/2024] [Indexed: 11/17/2024]
Abstract
Oxytocin research is rapidly evolving and increasingly reveals that epigenetic modifications to the oxytocin receptor gene (OXTR) are functional, plastic, and reliable components of oxytocinergic system function. This review outlines how OXTR epigenetics are shaped by the early life environment, impact social-developmental outcomes, and have strong potential to serve as therapeutic targets. We first establish the malleability of OXTR epigenetics in infancy in both animal models and humans through research demonstrating the impact of the early life environment on OXTR DNA methylation (OXTRm) and subsequent social behavior. Next, we detail how OXTRm serves as a predictive mechanism for neurodevelopmental outcomes in animal models of social behavior such as the prairie vole, and summarize the role of OXTRm in psychiatric disorders, emotional processing, and attachment behavior in humans. We discuss the potential of further OXTRm research to improve oxytocin therapeutics by highlighting how a deeper knowledge of OXTRm could improve the therapeutic potential of exogenous oxytocin, how OXTRm may impact additional cellular mechanisms with therapeutic potential including control of the perinatal GABA switch, and how early life therapies may target the tuning of endogenous OXTRm. Finally, we review limitations of previous oxytocin research and make recommendations for future research. IMPACT: Previous research into oxytocin therapeutics has been hampered by methodological difficulties that may be improved by assay of the oxytocin receptor gene (OXTR) and its methylation (OXTRm) Key sites of OXTRm modification link early life exposures to developmental and behavioral outcomes OXTRm appears to have a critical period of development in early life Epigenetic modification of the oxytocin receptor gene could serve as a powerful target for therapeutic interventions.
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Affiliation(s)
- Madelyn G Nance
- Department of Neurology, University of Virginia, Charlottesville, VA, USA
| | - Kelsey M Sullivan
- Department of Pediatrics, Division of Neonatology, University of Virginia, Charlottesville, VA, USA.
| | - Meghan H Puglia
- Department of Neurology, University of Virginia, Charlottesville, VA, USA
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2
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Baudat M, Joosten EAJ, Simons SHP. Repetitive daily oxytocin treatment reduces weight gain but not acute neonatal procedural pain. Pediatr Res 2024:10.1038/s41390-024-03680-9. [PMID: 39523390 DOI: 10.1038/s41390-024-03680-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/09/2024] [Accepted: 10/08/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND While the incidence of neonatal intensive care unit (NICU) admission steadily increases, neonatology lacks evidence of a safe, effective, and preventive analgesic for treating procedural pain. Given its role in nociception and promoting healthy neurodevelopment, the endogenous neuropeptide oxytocin (OT) emerges as a promising candidate. METHODS This study investigates the use of daily repeated subcutaneous OT (1 mg/kg) treatment in an established model of neonatal repetitive procedural pain and assesses the effectivity of OT treatment on mechanical sensitivity and body weight. RESULTS Contrary to our hypothesis repeated daily OT treatment did not prevent the development of mechanical hypersensitivity following needle pricks. Furthermore, treatment with OT diminished body weight gain in neonatal pups, a major side effect observed throughout the neonatal week. These results highlight the unique nature of the maturing nociceptive system that makes the identification and selection of analgesic options for the treatment of acute neonatal procedural pain a major challenge. CONCLUSION In conclusion, our preclinical results do not support the use of repeated OT for acute pain relief in the NICU, and the side effects on body weight gain raise concerns about the use of OT in the NICU. IMPACT Repeated daily OT treatment inhibits weight gain in neonatal rat pus. Repetitive daily OT administration does not prevent the development of mechanical hypersensitivity in a model of neonatal procedural pain. Future research must focus on the unique physiology of the developing nociceptive system to establish safe, effective and protective treatment of neonatal procedural pain.
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Affiliation(s)
- Mathilde Baudat
- Department of Anesthesiology and Pain Management, Maastricht University Medical Centre+, Maastricht, the Netherlands.
- Department of Translational Neuroscience, Institute of Mental Health and Neuroscience Research, Maastricht University, Maastricht, the Netherlands.
| | - Elbert A J Joosten
- Department of Anesthesiology and Pain Management, Maastricht University Medical Centre+, Maastricht, the Netherlands
- Department of Translational Neuroscience, Institute of Mental Health and Neuroscience Research, Maastricht University, Maastricht, the Netherlands
| | - Sinno H P Simons
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus University Medical Centre Rotterdam- Sophia Children Hospital, Rotterdam, the Netherlands
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3
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Bonthron C, Burley S, Broadhead MJ, Metodieva V, Grant SGN, Chandran S, Miles GB. Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS. PLoS One 2024; 19:e0306423. [PMID: 39088455 PMCID: PMC11293752 DOI: 10.1371/journal.pone.0306423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 06/17/2024] [Indexed: 08/03/2024] Open
Abstract
Hyperexcitability of motor neurons and spinal cord motor circuitry has been widely reported in the early stages of Amyotrophic Lateral Sclerosis (ALS). Changes in the relative amount of excitatory to inhibitory inputs onto a neuron (E:I synaptic ratio), possibly through a developmental shift in synapse formation in favour of excitatory transmission, could underlie pathological hyperexcitability. Given that astrocytes play a major role in early synaptogenesis and are implicated in ALS pathogenesis, their potential contribution to disease mechanisms involving synaptic imbalances and subsequent hyperexcitability is also of great interest. In order to assess E:I ratios in ALS, we utilised a novel primary spinal neuron / astrocyte co-culture system, derived from neonatal mice, in which synapses are formed in vitro. Using multiple ALS mouse models we found that no combination of astrocyte or neuron genotype produced alterations in E:I synaptic ratios assessed using pre- and post-synaptic anatomical markers. Similarly, we observed that ephrin-B1, a major contact-dependent astrocytic synaptogenic protein, was not differentially expressed by ALS primary astrocytes. Further to this, analysis of E:I ratios across the entire grey matter of the lumbar spinal cord in young (post-natal day 16-19) ALS mice revealed no differences versus controls. Finally, analysis in co-cultures of human iPSC-derived motor neurons and astrocytes harbouring the pathogenic C9orf72 hexanucleotide repeat expansion showed no evidence of a bias toward excitatory versus inhibitory synapse formation. We therefore conclude, utilising multiple ALS models, that we do not observe significant changes in the relative abundance of excitatory versus inhibitory synapses as would be expected if imbalances in synaptic inputs contribute to early hyperexcitability.
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Affiliation(s)
- Calum Bonthron
- School of Psychology and Neuroscience, University of St Andrews, St Andrews, United Kingdom
| | - Sarah Burley
- School of Psychology and Neuroscience, University of St Andrews, St Andrews, United Kingdom
- School of Biology, University of St Andrews, St Andrews, United Kingdom
| | - Matthew J. Broadhead
- School of Psychology and Neuroscience, University of St Andrews, St Andrews, United Kingdom
| | - Vanya Metodieva
- School of Biology, University of St Andrews, St Andrews, United Kingdom
- Centre of Biophotonics, University of St Andrews, St Andrews, United Kingdom
| | - Seth G. N. Grant
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Simons Initiative for the Developing Brain (SIDB), Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Siddharthan Chandran
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Simons Initiative for the Developing Brain (SIDB), Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
- UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
- Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom
| | - Gareth B. Miles
- School of Psychology and Neuroscience, University of St Andrews, St Andrews, United Kingdom
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4
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Schill DJ, Attili D, DeLong CJ, McInnis MG, Johnson CN, Murphy GG, O’Shea KS. Human-Induced Pluripotent Stem Cell (iPSC)-Derived GABAergic Neuron Differentiation in Bipolar Disorder. Cells 2024; 13:1194. [PMID: 39056776 PMCID: PMC11275104 DOI: 10.3390/cells13141194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 06/28/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
Bipolar disorder (BP) is a recurring psychiatric condition characterized by alternating episodes of low energy (depressions) followed by manias (high energy). Cortical network activity produced by GABAergic interneurons may be critical in maintaining the balance in excitatory/inhibitory activity in the brain during development. Initially, GABAergic signaling is excitatory; with maturation, these cells undergo a functional switch that converts GABAA channels from depolarizing (excitatory) to hyperpolarizing (inhibitory), which is controlled by the intracellular concentration of two chloride transporters. The earliest, NKCC1, promotes chloride entry into the cell and depolarization, while the second (KCC2) stimulates movement of chloride from the neuron, hyperpolarizing it. Perturbations in the timing or expression of NKCC1/KCC2 may affect essential morphogenetic events including cell proliferation, migration, synaptogenesis and plasticity, and thereby the structure and function of the cortex. We derived induced pluripotent stem cells (iPSC) from BP patients and undiagnosed control (C) individuals, then modified a differentiation protocol to form GABAergic interneurons, harvesting cells at sequential stages of differentiation. qRT-PCR and RNA sequencing indicated that after six weeks of differentiation, controls transiently expressed high levels of NKCC1. Using multi-electrode array (MEA) analysis, we observed that BP neurons exhibit increased firing, network bursting and decreased synchrony compared to C. Understanding GABA signaling in differentiation may identify novel approaches and new targets for treatment of neuropsychiatric disorders such as BP.
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Affiliation(s)
- Daniel J. Schill
- Department of Cell and Developmental Biology, The University of Michigan, Ann Arbor, MI 48109, USA; (D.A.); (C.J.D.); (C.N.J.); (K.S.O.)
| | - Durga Attili
- Department of Cell and Developmental Biology, The University of Michigan, Ann Arbor, MI 48109, USA; (D.A.); (C.J.D.); (C.N.J.); (K.S.O.)
| | - Cynthia J. DeLong
- Department of Cell and Developmental Biology, The University of Michigan, Ann Arbor, MI 48109, USA; (D.A.); (C.J.D.); (C.N.J.); (K.S.O.)
| | - Melvin G. McInnis
- Department of Psychiatry, The University of Michigan, Ann Arbor, MI 48109, USA;
| | - Craig N. Johnson
- Department of Cell and Developmental Biology, The University of Michigan, Ann Arbor, MI 48109, USA; (D.A.); (C.J.D.); (C.N.J.); (K.S.O.)
| | - Geoffrey G. Murphy
- Department of Molecular and Integrative Physiology, The University of Michigan, Ann Arbor, MI 48109, USA;
| | - K. Sue O’Shea
- Department of Cell and Developmental Biology, The University of Michigan, Ann Arbor, MI 48109, USA; (D.A.); (C.J.D.); (C.N.J.); (K.S.O.)
- Department of Psychiatry, The University of Michigan, Ann Arbor, MI 48109, USA;
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Topchiy I, Mohbat J, Folorunso OO, Wang ZZ, Lazcano-Etchebarne C, Engin E. GABA system as the cause and effect in early development. Neurosci Biobehav Rev 2024; 161:105651. [PMID: 38579901 PMCID: PMC11081854 DOI: 10.1016/j.neubiorev.2024.105651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 03/05/2024] [Accepted: 04/01/2024] [Indexed: 04/07/2024]
Abstract
GABA is the primary inhibitory neurotransmitter in the adult brain and through its actions on GABAARs, it protects against excitotoxicity and seizure activity, ensures temporal fidelity of neurotransmission, and regulates concerted rhythmic activity of neuronal populations. In the developing brain, the development of GABAergic neurons precedes that of glutamatergic neurons and the GABA system serves as a guide and framework for the development of other brain systems. Despite this early start, the maturation of the GABA system also continues well into the early postnatal period. In this review, we organize evidence around two scenarios based on the essential and protracted nature of GABA system development: 1) disruptions in the development of the GABA system can lead to large scale disruptions in other developmental processes (i.e., GABA as the cause), 2) protracted maturation of this system makes it vulnerable to the effects of developmental insults (i.e., GABA as the effect). While ample evidence supports the importance of GABA/GABAAR system in both scenarios, large gaps in existing knowledge prevent strong mechanistic conclusions.
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Affiliation(s)
- Irina Topchiy
- Division of Basic Neuroscience, McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA
| | - Julie Mohbat
- Division of Basic Neuroscience, McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA; School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Lausanne CH-1015, Switzerland
| | - Oluwarotimi O Folorunso
- Division of Basic Neuroscience, McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA
| | - Ziyi Zephyr Wang
- Division of Basic Neuroscience, McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA
| | | | - Elif Engin
- Division of Basic Neuroscience, McLean Hospital, Belmont, MA 02478, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA.
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Devlin BA, Nguyen DM, Grullon G, Clark MJ, Ceasrine AM, Deja M, Shah A, Ati S, Finn A, Ribeiro D, Schaefer A, Bilbo SD. Neuron Derived Cytokine Interleukin-34 Controls Developmental Microglia Function. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.10.589920. [PMID: 38766127 PMCID: PMC11100801 DOI: 10.1101/2024.05.10.589920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Neuron-microglia interactions dictate the development of neuronal circuits in the brain. However, the factors that support and broadly regulate these processes across developmental stages are largely unknown. Here, we find that IL34, a neuron-derived cytokine, is upregulated in development and plays a critical role in supporting and maintaining neuroprotective, mature microglia in the anterior cingulate cortex (ACC) of mice. We show that IL34 mRNA and protein is upregulated in neurons in the second week of postnatal life and that this increase coincides with increases in microglia number and expression of mature, homeostatic markers, e.g., TMEM119. We also found that IL34 mRNA is higher in more active neurons, and higher in excitatory (compared to inhibitory) neurons. Genetic KO of IL34 prevents the functional maturation of microglia and results in an anxiolytic phenotype in these mice by adulthood. Acute, low dose blocking of IL34 at postnatal day (P)15 in mice decreased microglial TMEM119 expression and increased aberrant microglial phagocytosis of thalamocortical synapses within the ACC. In contrast, viral overexpression of IL34 early in life (P1-P8) caused early maturation of microglia and prevented microglial phagocytosis of thalamocortical synapses during the appropriate neurodevelopmental refinement window. Taken together, these findings establish IL34 as a key regulator of neuron-microglia crosstalk in postnatal brain development, controlling both microglial maturation and synapse engulfment.
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7
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Fadaei-Kenarsary M, Esmaeilpour K, Shabani M, Sheibani V. Maternal Substance Use and Early-Life Adversity: Inducing Drug Dependence in Offspring, Interactions, Mechanisms, and Treatments. ADDICTION & HEALTH 2024; 16:51-66. [PMID: 38651025 PMCID: PMC11032613 DOI: 10.34172/ahj.2024.1478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 08/11/2023] [Indexed: 04/25/2024]
Abstract
The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal addiction because of the separation. Maternal separation (MS) leads to the development of behavioural and neuropsychiatric issues in the future. Despite the importance of this issue, empirical investigations of the influences of maternal substance use and separation on substance use problems in offspring are limited, and studies that consider both effects are rare. This study aims to review a few studies on the mechanisms, treatments, genetics, epigenetics, molecular and psychological alterations, and neuroanatomical regions involved in the dependence of offspring who underwent maternal addiction and separation. The PubMed database was used. A total of 95 articles were found, including the most related ones in the review. The brain's lateral paragigantocellularis (LPGi), nucleus accumbens (NAc), caudate-putamen (CPu), prefrontal cortex (PFC), and hippocampus, can be affected by MS. Dopamine receptor subtype genes, alcohol biomarker minor allele, and preproenkephalin mRNA may be affected by alcohol or substance use disorders. After early-life adversity, histone acetylation in the hippocampus may be linked to brain-derived neurotrophic factor (BDNF) gene epigenetics and glucocorticoid receptors (GRs). The adverse early-life experiences differ in offspring›s genders and rewire the brain›s dopamine and endocannabinoid circuits, making offspring more susceptible to dependence. Related psychological factors rooted in early-life stress (ELS) and parental substance use disorder (SUD). Treatments include antidepressants, histone deacetylase inhibitors, lamotrigine, ketamine, choline, modafinil, methadone, dopamine, cannabinoid 1 receptor agonists/antagonists, vitamins, oxytocin, tetrahydrocannabinol, SR141716A, and dronabinol. Finally, the study emphasizes the need for multifaceted strategies to prevent these outcomes.
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Affiliation(s)
- Maysam Fadaei-Kenarsary
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Khadijeh Esmaeilpour
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Health Sciences, Faculty of Health, University of Waterloo, Waterloo, Ontario, Canada
| | - Mohammad Shabani
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Vahid Sheibani
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
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8
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McArdle CJ, Arnone AA, Heaney CF, Raab-Graham KF. A paradoxical switch: the implications of excitatory GABAergic signaling in neurological disorders. Front Psychiatry 2024; 14:1296527. [PMID: 38268565 PMCID: PMC10805837 DOI: 10.3389/fpsyt.2023.1296527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 12/04/2023] [Indexed: 01/26/2024] Open
Abstract
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. In the mature brain, inhibitory GABAergic signaling is critical in maintaining neuronal homeostasis and vital human behaviors such as cognition, emotion, and motivation. While classically known to inhibit neuronal function under physiological conditions, previous research indicates a paradoxical switch from inhibitory to excitatory GABAergic signaling that is implicated in several neurological disorders. Various mechanisms have been proposed to contribute to the excitatory switch such as chloride ion dyshomeostasis, alterations in inhibitory receptor expression, and modifications in GABAergic synaptic plasticity. Of note, the hypothesized mechanisms underlying excitatory GABAergic signaling are highlighted in a number of neurodevelopmental, substance use, stress, and neurodegenerative disorders. Herein, we present an updated review discussing the presence of excitatory GABAergic signaling in various neurological disorders, and their potential contributions towards disease pathology.
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Affiliation(s)
- Colin J. McArdle
- Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Alana A. Arnone
- Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
- Department of General Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Chelcie F. Heaney
- Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Kimberly F. Raab-Graham
- Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
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Soma C, Hitomi S, Oshima E, Hayashi Y, Soma K, Shibuta I, Tsuboi Y, Shirakawa T, Kikuiri T, Iwata K, Shinoda M. Involvement of oxidative stress in orofacial mechanical pain hypersensitivity following neonatal maternal separation in rats. Sci Rep 2023; 13:22760. [PMID: 38123836 PMCID: PMC10733350 DOI: 10.1038/s41598-023-50116-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 12/15/2023] [Indexed: 12/23/2023] Open
Abstract
Patients with persistent pain have sometimes history of physical abuse or neglect during infancy. However, the pathogenic mechanisms underlying orofacial pain hypersensitivity associated with early-life stress remain unclear. The present study focused on oxidative stress and investigated its role in pain hypersensitivity in adulthood following early-life stress. To establish an early-life stress model, neonatal pups were separated with their mother in isolated cages for 2 weeks. The mechanical head-withdrawal threshold (MHWT) in the whisker pad skin of rats received maternal separation (MS) was lower than that of non-MS rats at postnatal week 7. In MS rats, the expression of 8-hydroxy-deoxyguanosine, a marker of DNA oxidative damage, was enhanced, and plasma antioxidant capacity, but not mitochondrial complex I activity, decreased compared with that in non-MS rats. Reactive oxygen species (ROS) inactivation and ROS-sensitive transient receptor potential ankyrin 1 (TRPA1) antagonism in the whisker pad skin at week 7 suppressed the decrease of MHWT. Corticosterone levels on day 14 increased in MS rats. Corticosterone receptor antagonism during MS periods suppressed the reduction in antioxidant capacity and MHWT. The findings suggest that early-life stress potentially induces orofacial mechanical pain hypersensitivity via peripheral nociceptor TRPA1 hyperactivation induced by oxidative stress in the orofacial region.
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Affiliation(s)
- Chihiro Soma
- Department of Pediatric Dentistry, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan
- Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Suzuro Hitomi
- Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan.
| | - Eri Oshima
- Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
| | - Yoshinori Hayashi
- Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Kumi Soma
- Department of Pediatric Dentistry, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Ikuko Shibuta
- Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Yoshiyuki Tsuboi
- Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Tetsuo Shirakawa
- Department of Pediatric Dentistry, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Takashi Kikuiri
- Department of Pediatric Dentistry, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Koichi Iwata
- Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Masamichi Shinoda
- Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo, 101-8310, Japan
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Tomita K, Kuwahara Y, Igarashi K, Kitanaka J, Kitanaka N, Takashi Y, Tanaka KI, Roudkenar MH, Roushandeh AM, Kurimasa A, Nishitani Y, Sato T. Therapeutic potential for KCC2-targeted neurological diseases. JAPANESE DENTAL SCIENCE REVIEW 2023; 59:431-438. [PMID: 38022385 PMCID: PMC10665825 DOI: 10.1016/j.jdsr.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 11/01/2023] [Accepted: 11/05/2023] [Indexed: 12/01/2023] Open
Abstract
Patients with neurological diseases, such as schizophrenia, tend to show low K+-Cl- co-transporter 2 (KCC2) levels in the brain. The cause of these diseases has been associated with stress and neuroinflammation. However, since the pathogenesis of these diseases is not yet fully investigated, drug therapy is still limited to symptomatic therapy. Targeting KCC2, which is mainly expressed in the brain, seems to be an appropriate approach in the treatment of these diseases. In this review, we aimed to discuss about stress and inflammation, KCC2 and Gamma-aminobutyric acid (GABA) function, diseases which decrease the KCC2 levels in the brain, factors that regulate KCC2 activity, and the possibility to overcome neuronal dysfunction targeting KCC2. We also aimed to discuss the relationships between neurological diseases and LPS caused by Porphyromonas gingivalis (P. g), which is a type of oral bacterium. Clinical trials on oxytocin, sirtuin 1 (SIRT1) activator, and transient receptor potential cation channel subfamily V Member 1 activator have been conducted to develop effective treatment methods. We believe that KCC2 modulators that regulate mitochondria, such as oxytocin, glycogen synthase kinase 3β (GSK3β), and SIRT1, can be potential targets for neurological diseases.
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Affiliation(s)
- Kazuo Tomita
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890–8544, Japan
- Division of Pharmacology, Department of Pharmacy, School of Pharmacy, Hyogo Medical University, Hyogo 650–8530, Japan
| | - Yoshikazu Kuwahara
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890–8544, Japan
- Division of Radiation Biology and Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Miyagi, 983-8536, Japan
| | - Kento Igarashi
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890–8544, Japan
- Division of Pharmacology, Department of Pharmacy, School of Pharmacy, Hyogo Medical University, Hyogo 650–8530, Japan
| | - Junichi Kitanaka
- Laboratory of Drug Addiction and Experimental Therapeutics, Schoolof Pharmacy, Hyogo Medical University, Hyogo 650-8530, Japan
| | - Nobue Kitanaka
- Laboratory of Drug Addiction and Experimental Therapeutics, Schoolof Pharmacy, Hyogo Medical University, Hyogo 650-8530, Japan
- Department of Pharmacology, School of Medicine, Hyogo Medical University, Hyogo 663-8501, Japan
| | - Yuko Takashi
- Department of Restorative Dentistry and Endodontology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890–8544, Japan
| | - Koh-ichi Tanaka
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890–8544, Japan
- Division of Pharmacology, Department of Pharmacy, School of Pharmacy, Hyogo Medical University, Hyogo 650–8530, Japan
| | - Mehryar Habibi Roudkenar
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890–8544, Japan
- Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht 41937–13194, Iran
| | - Amaneh Mohammadi Roushandeh
- Department of Anatomy, School of Biomedical Sciences, Medicine & Health, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Akihiro Kurimasa
- Division of Radiation Biology and Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Miyagi, 983-8536, Japan
| | - Yoshihiro Nishitani
- Department of Restorative Dentistry and Endodontology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890–8544, Japan
| | - Tomoaki Sato
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890–8544, Japan
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11
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Machado DN, Durán-Carabali LE, Odorcyk FK, Carvalho AVS, Martini APR, Schlemmer LM, de Mattos MDM, Bernd GP, Dalmaz C, Netto CA. Bumetanide Attenuates Cognitive Deficits and Brain Damage in Rats Subjected to Hypoxia-Ischemia at Two Time Points of the Early Postnatal Period. Neurotox Res 2023; 41:526-545. [PMID: 37378827 DOI: 10.1007/s12640-023-00654-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 05/24/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023]
Abstract
Neonatal hypoxia-ischemia (HI) is one of the main causes of tissue damage, cell death, and imbalance between neuronal excitation and inhibition and synaptic loss in newborns. GABA, the major inhibitory neurotransmitter of the central nervous system (CNS) in adults, is excitatory at the onset of neurodevelopment and its action depends on the chloride (Cl-) cotransporters NKCC1 (imports Cl-) and KCC2 (exports Cl-) expression. Under basal conditions, the NKCC1/KCC2 ratio decreases over neurodevelopment. Thus, changes in this ratio caused by HI may be related to neurological disorders. The present study evaluated the effects of bumetanide (NKCC cotransporters inhibitor) on HI impairments in two neurodevelopmental periods. Male Wistar rat pups, 3 (PND3) and 11 (PND11) days old, were submitted to the Rice-Vannucci model. Animals were divided into 3 groups: SHAM, HI-SAL, and HI-BUM, considering each age. Bumetanide was administered intraperitoneally at 1, 24, 48, and 72 h after HI. NKCC1, KCC2, PSD-95, and synaptophysin proteins were analyzed after the last injection by western blot. Negative geotaxis, righting reflex, open field, object recognition test, and Morris water maze task were performed to assess neurological reflexes, locomotion, and memory function. Tissue atrophy and cell death were evaluated by histology. Bumetanide prevented neurodevelopmental delay, hyperactivity, and declarative and spatial memory deficits. Furthermore, bumetanide reversed HI-induced brain tissue damage, reduced neuronal death and controlled GABAergic tone, maintained the NKCC1/KCC2 ratio, and synaptogenesis close to normality. Thereby, bumetanide appears to play an important therapeutic role in the CNS, protecting the animals against HI damage and improving functional performance.
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Affiliation(s)
- Diorlon Nunes Machado
- Graduate Program in Biological Sciences: Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos, 2600, Porto Alegre, RS, CEP: 90035-003, Brazil.
| | - Luz Elena Durán-Carabali
- Graduate Program in Biological Sciences: Physiology, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Felipe Kawa Odorcyk
- Graduate Program in Biological Sciences: Physiology, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Andrey Vinicios Soares Carvalho
- Graduate Program in Biological Sciences: Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos, 2600, Porto Alegre, RS, CEP: 90035-003, Brazil
| | - Ana Paula Rodrigues Martini
- Graduate Program in Biological Sciences: Neuroscience, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Livia Machado Schlemmer
- Graduate Program in Biological Sciences: Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos, 2600, Porto Alegre, RS, CEP: 90035-003, Brazil
| | - Marcel de Medeiros de Mattos
- Graduate Program in Biological Sciences: Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos, 2600, Porto Alegre, RS, CEP: 90035-003, Brazil
| | - Gabriel Pereira Bernd
- Graduate Program in Biological Sciences: Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos, 2600, Porto Alegre, RS, CEP: 90035-003, Brazil
| | - Carla Dalmaz
- Departament of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Carlos Alexandre Netto
- Departament of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Departament of Physiology, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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12
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Abstract
Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy, intellectual disability, autistic features, speech deficits, and sleep and breathing abnormalities. Neurologically, patients with all three disorders display microcephaly, aberrant dendritic morphology, reduced spine density, and an imbalance of excitatory/inhibitory signaling. Loss-of-function mutations in the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1 genes also cause similar behavioral and neurobiological defects and were referred to as congenital or variant Rett syndrome. The relatively recent realization that CDKL5 deficiency disorder (CDD), FOXG1 syndrome, and Rett syndrome are distinct neurodevelopmental disorders with some distinctive features have resulted in separate focus being placed on each disorder with the assumption that distinct molecular mechanisms underlie their pathogenesis. However, given that many of the core symptoms and neurological features are shared, it is likely that the disorders share some critical molecular underpinnings. This review discusses the possibility that deregulation of common molecules in neurons and astrocytes plays a central role in key behavioral and neurological abnormalities in all three disorders. These include KCC2, a chloride transporter, vGlut1, a vesicular glutamate transporter, GluD1, an orphan-glutamate receptor subunit, and PSD-95, a postsynaptic scaffolding protein. We propose that reduced expression or activity of KCC2, vGlut1, PSD-95, and AKT, along with increased expression of GluD1, is involved in the excitatory/inhibitory that represents a key aspect in all three disorders. In addition, astrocyte-derived brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and inflammatory cytokines likely affect the expression and functioning of these molecules resulting in disease-associated abnormalities.
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Affiliation(s)
- Santosh R D’Mello
- Department of Biological Sciences, Louisiana State University Shreveport, Shreveport, LA 71104, USA
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13
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Holuka C, Morel C, Roth S, Lamartinière Y, Mériaux SB, Paoli J, Guébels P, Duca RC, Godderis L, van Nieuwenhuyse A, Kremarik-Bouillaud P, Cariou R, Emond C, Schroeder H, Turner JD, Grova N. The epigenetic hallmark of early-life α-hexabromocyclododecane exposure: From cerebellar 6-mA levels to locomotor performance in adulthood. ENVIRONMENT INTERNATIONAL 2023; 178:108103. [PMID: 37494814 DOI: 10.1016/j.envint.2023.108103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 07/18/2023] [Accepted: 07/18/2023] [Indexed: 07/28/2023]
Abstract
There is a growing evidence that methylation at the N6 position of adenine (6-mA), whose modulation occurs primarily during development, would be a reliable epigenetic marker in eukaryotic organisms. The present study raises the question as to whether early-life exposure to α-hexabromocyclododecane (α-HBCDD), a brominated flame retardant, may trigger modifications in 6-mA epigenetic hallmarks in the brain during the development which, in turn could affect the offspring behaviour in adulthood. Pregnant Wistar rats were split into two groups: control and α-HBCDD (66 ng/kg/per os, G0-PND14). At PND1, α-HBCDD levels were assessed in brain and liver by LC-MS/MS. At PND14, DNA was isolated from the offspring's cerebellum. DNA methylation was measured by 6-mA-specific immunoprecipitation and Illumina® sequencing (MEDIP-Seq). Locomotor activity was finally evaluated at PND120. In our early-life exposure model, we confirmed that α-HBCDD can cross the placental barrier and be detected in pups at birth. An obvious post-exposure phenotype with locomotor deficits was observed when the rats reached adulthood. This was accompanied by sex-specific over-methylation of genes involved in the insulin signaling pathway, MAPK signaling pathway as well as serotonergic and GABAergic synapses, potentially altering the normal process of neurodevelopment with consequent motor impairments crystalized at adulthood.
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Affiliation(s)
- Cyrielle Holuka
- Immune Endocrine Epigenetics Research Group, Department of Infection and Immunity-Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-Sur-Alzette, Luxembourg; Faculty of Science, University of Luxembourg, L-4365 Belval, Luxembourg.
| | - Chloé Morel
- Calbinotox, Faculty of Science and Technology, University of Lorraine, Campus Aiguillettes, B.P. 70239, 54506 Vandoeuvre-lès-Nancy, France.
| | - Sarah Roth
- Immune Endocrine Epigenetics Research Group, Department of Infection and Immunity-Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-Sur-Alzette, Luxembourg.
| | - Yordenca Lamartinière
- Calbinotox, Faculty of Science and Technology, University of Lorraine, Campus Aiguillettes, B.P. 70239, 54506 Vandoeuvre-lès-Nancy, France.
| | - Sophie B Mériaux
- Immune Endocrine Epigenetics Research Group, Department of Infection and Immunity-Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-Sur-Alzette, Luxembourg.
| | - Justine Paoli
- Calbinotox, Faculty of Science and Technology, University of Lorraine, Campus Aiguillettes, B.P. 70239, 54506 Vandoeuvre-lès-Nancy, France.
| | - Pauline Guébels
- Immune Endocrine Epigenetics Research Group, Department of Infection and Immunity-Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-Sur-Alzette, Luxembourg.
| | - Radu C Duca
- Department of Health Protection, National Health Laboratory (LNS), Dudelange, Luxembourg; Centre for Environment and Health, University of Leuven (KU Leuven), Leuven, Belgium.
| | - Lode Godderis
- Centre for Environment and Health, University of Leuven (KU Leuven), Leuven, Belgium; IDEWE, External Service for Prevention and Protection at Work, Heverlee 3001, Belgium.
| | - An van Nieuwenhuyse
- Department of Health Protection, National Health Laboratory (LNS), Dudelange, Luxembourg; Centre for Environment and Health, University of Leuven (KU Leuven), Leuven, Belgium.
| | - Pascaline Kremarik-Bouillaud
- UMR Inserm 1256 nGERE, Nutrition-Génétique et exposition aux risques environnementaux, Institute of Medical Research (Pôle BMS), University of Lorraine, B.P. 184, 54511 Nancy, France.
| | | | - Claude Emond
- PKSH Inc., Crabtree, Quebec, Canada; School of Public Health, DSEST, University of Montreal, Montreal, Quebec, Canada.
| | - Henri Schroeder
- Calbinotox, Faculty of Science and Technology, University of Lorraine, Campus Aiguillettes, B.P. 70239, 54506 Vandoeuvre-lès-Nancy, France; UMR Inserm 1256 nGERE, Nutrition-Génétique et exposition aux risques environnementaux, Institute of Medical Research (Pôle BMS), University of Lorraine, B.P. 184, 54511 Nancy, France.
| | - Jonathan D Turner
- Immune Endocrine Epigenetics Research Group, Department of Infection and Immunity-Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-Sur-Alzette, Luxembourg.
| | - Nathalie Grova
- Immune Endocrine Epigenetics Research Group, Department of Infection and Immunity-Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-Sur-Alzette, Luxembourg; Calbinotox, Faculty of Science and Technology, University of Lorraine, Campus Aiguillettes, B.P. 70239, 54506 Vandoeuvre-lès-Nancy, France; UMR Inserm 1256 nGERE, Nutrition-Génétique et exposition aux risques environnementaux, Institute of Medical Research (Pôle BMS), University of Lorraine, B.P. 184, 54511 Nancy, France.
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14
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Igarashi K, Kuchiiwa S, Kuchiiwa T, Tomita K, Sato T. Comparative data on emotional (psychotic) aggressive biting behavior in mice of ddY strain measured by using two devices; Aggressive response meter and powerlab-compatible type aggressive response meter. Data Brief 2023; 48:109231. [PMID: 37383814 PMCID: PMC10294006 DOI: 10.1016/j.dib.2023.109231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 05/08/2023] [Indexed: 06/30/2023] Open
Abstract
The Aggressive Response Meter (ARM) has been validated for measuring emotional (psychotic) aggression triggered by mental irritation in mice. In the present article, we newly developed a device, pARM (PowerLab-compatible type ARM). We collected on the aggressive biting behavior (ABB) intensity and ABB frequency of 20 male and female mice of ddY strain studied over a period of 6 days by using pARM and the former ARM. We calculated Pearson's correlation between the values of pARM and those of ARM. The accumulated data can be referred as a basis for demonstrating the consistence of pARM and the former ARM, and used in future research to augment the understanding of stress-induced emotional aggression in mice.
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Affiliation(s)
- Kento Igarashi
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Satoshi Kuchiiwa
- Department of Morphological Science, Field of Neurology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Toshiko Kuchiiwa
- Department of Morphological Science, Field of Neurology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
- Department of Clinical Psychology, Graduate School of Human Science, Kagoshima Immaculate Herat University, 2365 Amatatsu-Cho, Satsuma-Sendai, Kagoshima 895-0011, Japan
| | - Kazuo Tomita
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Tomoaki Sato
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
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15
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Karst H, Droogers WJ, van der Weerd N, Damsteegt R, van Kroonenburg N, Sarabdjitsingh RA, Joëls M. Acceleration of GABA-switch after early life stress changes mouse prefrontal glutamatergic transmission. Neuropharmacology 2023; 234:109543. [PMID: 37061088 DOI: 10.1016/j.neuropharm.2023.109543] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/06/2023] [Accepted: 04/09/2023] [Indexed: 04/17/2023]
Abstract
Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later in life. The EI-balance is (amongst others) influenced by the switch of GABAergic transmission from excitatory to inhibitory, the so-called "GABA-switch". Here, we investigated how ELS affects the GABA-switch in mouse infralimbic Prefrontal Cortex layer 2/3 neurons, using the limited-nesting-and-bedding model. In ELS mice, the GABA-switch occurred already between postnatal day (P) 6 and P9, as opposed to P15-P21 in controls. This was associated with increased expression of the inward chloride transporter NKCC1, compared to the outward chloride transporter KCC2, both of which are important for the intracellular chloride concentration and, hence, the GABA reversal potential (Erev). Chloride transporters are not only important for regulating chloride concentration postsynaptically, but also presynaptically. Depending on the Erev of GABA, presynaptic GABAA receptor stimulation causes a depolarization or hyperpolarization, and thereby enhanced or reduced fusion of glutamate vesicles respectively, in turn changing the frequency of miniature postsynaptic currents (mEPSCs). In accordance, bumetanide, a blocker of NKCC1, shifted the Erev GABA towards more hyperpolarized levels in P9 control mice and reduced the mEPSC frequency. Other modulators of chloride transporters, e.g. VU0463271 (a KCC2 antagonist) and aldosterone -which increases NKCC1 expression-did not affect postsynaptic Erev in ELS P9 mice, but did increase the mEPSC frequency. We conclude that the mouse GABA-switch is accelerated after ELS, affecting both the pre- and postsynaptic chloride homeostasis, the former altering glutamatergic transmission. This may considerably affect brain development.
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Affiliation(s)
- Henk Karst
- Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands.
| | - Wouter J Droogers
- Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Nelleke van der Weerd
- Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Ruth Damsteegt
- Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Nicky van Kroonenburg
- Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - R Angela Sarabdjitsingh
- Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Marian Joëls
- Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands; University Medical Center Groningen, University of Groningen, the Netherlands
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16
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Using SuperClomeleon to Measure Changes in Intracellular Chloride during Development and after Early Life Stress. eNeuro 2022; 9:ENEURO.0416-22.2022. [PMID: 36635254 PMCID: PMC9797207 DOI: 10.1523/eneuro.0416-22.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/25/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
Intraneuronal chloride concentrations ([Cl-]i) decrease during development resulting in a shift from depolarizing to hyperpolarizing GABA responses via chloride-permeable GABAA receptors. This GABA shift plays a pivotal role in postnatal brain development, and can be strongly influenced by early life experience. Here, we assessed the applicability of the recently developed fluorescent SuperClomeleon (SClm) sensor to examine changes in [Cl-]i using two-photon microscopy in brain slices. We used SClm mice of both sexes to monitor the developmental decrease in neuronal chloride levels in organotypic hippocampal cultures. We could discern a clear reduction in [Cl-]i between day in vitro (DIV)3 and DIV9 (equivalent to the second postnatal week in vivo) and a further decrease in some cells until DIV22. In addition, we assessed alterations in [Cl-]i in the medial prefrontal cortex (mPFC) of postnatal day (P)9 male SClm mouse pups after early life stress (ELS). ELS was induced by limiting nesting material between P2 and P9. ELS induced a shift toward higher (i.e., immature) chloride levels in layer 2/3 cells in the mPFC. Although conversion from SClm fluorescence to absolute chloride concentrations proved difficult, our study underscores that the SClm sensor is a powerful tool to measure physiological changes in [Cl-]i in brain slices.
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17
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The Role of Oxytocin in Abnormal Brain Development: Effect on Glial Cells and Neuroinflammation. Cells 2022; 11:cells11233899. [PMID: 36497156 PMCID: PMC9740972 DOI: 10.3390/cells11233899] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/07/2022] Open
Abstract
The neonatal period is critical for brain development and determinant for long-term brain trajectory. Yet, this time concurs with a sensitivity and risk for numerous brain injuries following perinatal complications such as preterm birth. Brain injury in premature infants leads to a complex amalgam of primary destructive diseases and secondary maturational and trophic disturbances and, as a consequence, to long-term neurocognitive and behavioral problems. Neuroinflammation is an important common factor in these complications, which contributes to the adverse effects on brain development. Mediating this inflammatory response forms a key therapeutic target in protecting the vulnerable developing brain when complications arise. The neuropeptide oxytocin (OT) plays an important role in the perinatal period, and its importance for lactation and social bonding in early life are well-recognized. Yet, novel functions of OT for the developing brain are increasingly emerging. In particular, OT seems able to modulate glial activity in neuroinflammatory states, but the exact mechanisms underlying this connection are largely unknown. The current review provides an overview of the oxytocinergic system and its early life development across rodent and human. Moreover, we cover the most up-to-date understanding of the role of OT in neonatal brain development and the potential neuroprotective effects it holds when adverse neural events arise in association with neuroinflammation. A detailed assessment of the underlying mechanisms between OT treatment and astrocyte and microglia reactivity is given, as well as a focus on the amygdala, a brain region of crucial importance for socio-emotional behavior, particularly in infants born preterm.
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18
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Hui KK, Chater TE, Goda Y, Tanaka M. How Staying Negative Is Good for the (Adult) Brain: Maintaining Chloride Homeostasis and the GABA-Shift in Neurological Disorders. Front Mol Neurosci 2022; 15:893111. [PMID: 35875665 PMCID: PMC9305173 DOI: 10.3389/fnmol.2022.893111] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 06/10/2022] [Indexed: 01/27/2023] Open
Abstract
Excitatory-inhibitory (E-I) imbalance has been shown to contribute to the pathogenesis of a wide range of neurodevelopmental disorders including autism spectrum disorders, epilepsy, and schizophrenia. GABA neurotransmission, the principal inhibitory signal in the mature brain, is critically coupled to proper regulation of chloride homeostasis. During brain maturation, changes in the transport of chloride ions across neuronal cell membranes act to gradually change the majority of GABA signaling from excitatory to inhibitory for neuronal activation, and dysregulation of this GABA-shift likely contributes to multiple neurodevelopmental abnormalities that are associated with circuit dysfunction. Whilst traditionally viewed as a phenomenon which occurs during brain development, recent evidence suggests that this GABA-shift may also be involved in neuropsychiatric disorders due to the "dematuration" of affected neurons. In this review, we will discuss the cell signaling and regulatory mechanisms underlying the GABA-shift phenomenon in the context of the latest findings in the field, in particular the role of chloride cotransporters NKCC1 and KCC2, and furthermore how these regulatory processes are altered in neurodevelopmental and neuropsychiatric disorders. We will also explore the interactions between GABAergic interneurons and other cell types in the developing brain that may influence the GABA-shift. Finally, with a greater understanding of how the GABA-shift is altered in pathological conditions, we will briefly outline recent progress on targeting NKCC1 and KCC2 as a therapeutic strategy against neurodevelopmental and neuropsychiatric disorders associated with improper chloride homeostasis and GABA-shift abnormalities.
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Affiliation(s)
- Kelvin K. Hui
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, United States
- Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Thomas E. Chater
- Laboratory for Synaptic Plasticity and Connectivity, RIKEN Center for Brain Science, Wako, Japan
| | - Yukiko Goda
- Laboratory for Synaptic Plasticity and Connectivity, RIKEN Center for Brain Science, Wako, Japan
- Synapse Biology Unit, Okinawa Institute for Science and Technology Graduate University, Onna, Japan
| | - Motomasa Tanaka
- Laboratory for Protein Conformation Diseases, RIKEN Center for Brain Science, Wako, Japan
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19
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Tomita K, Yamanishi-Taira S, Igarashi K, Oogai Y, Kuwahara Y, Roudkenar MH, Roushandeh AM, Miyawaki S, Kurimasa A, Sato T. Oxytocin ameliorates KCC2 decrease induced by oral bacteria-derived LPS that affect rat primary cultured cells and PC-12 cells. Peptides 2022; 150:170734. [PMID: 34974081 DOI: 10.1016/j.peptides.2021.170734] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/01/2021] [Accepted: 12/28/2021] [Indexed: 01/01/2023]
Abstract
Inflammation, especially neuroinflammation, which is caused by stress, leads to central nervous system (CNS) dysfunction. Because lipopolysaccharides (LPSs) cause neuroinflammation, we investigated the effect of LPSs to CNS. In PC-12 cells, LPSs derived from oral bacteria reduced the expression of KCC2, a Cl- transporter. LPS derived from P. gingivalis (P. g) administered to rat primary cultured cells also reduced the KCC2 expression. However, LPSs derived from E. coli did not reduce the KCC2 expression. LPS treatment activated TLR4, IL-1β, and REST gene expressions, which led to KCC2 inactivation in PC-12 cells. The mechanism of KCC2 has been shown to play an important role in brain maturation, function (such as the GABA switch), and behavioral problems, we investigated the GABA function. We found that the GABA function was changed from inhibitory to excitatory by the LPS derived from P. g treatment. We demonstrated that the GSK3β also involved in the KCC2 reduction by LPS treatment. We show that oxytocin rescued the reduction in KCC2 expression caused by LPSs by inhibiting GSK3β signaling but vasopressin could not. Considered together, our results indicate that the LPSs from oral bacteria but not the LPS from E. coli increase the risk for brain disorders and oxytocin might be a candidate to overcome the abnormal behavior caused by brain disorders such as psychiatric disorders.
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Affiliation(s)
- Kazuo Tomita
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
| | - Sayuri Yamanishi-Taira
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan; Department of Orthodontics and Dentofacial Orthopedics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Kento Igarashi
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yuichi Oogai
- Department of Oral Microbiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yoshikazu Kuwahara
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan; Division of Radiation Biology and Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Mehryar Habibi Roudkenar
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan; Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Parastar St., Rasht, 41887-94755, Iran
| | - Amaneh Mohammadi Roushandeh
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan; Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Parastar St., Rasht, 41887-94755, Iran
| | - Shouichi Miyawaki
- Department of Orthodontics and Dentofacial Orthopedics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Akihiro Kurimasa
- Division of Radiation Biology and Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Tomoaki Sato
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
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Savardi A, Borgogno M, De Vivo M, Cancedda L. Pharmacological tools to target NKCC1 in brain disorders. Trends Pharmacol Sci 2021; 42:1009-1034. [PMID: 34620512 DOI: 10.1016/j.tips.2021.09.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/27/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023]
Abstract
The chloride importer NKCC1 and the chloride exporter KCC2 are key regulators of neuronal chloride concentration. A defective NKCC1/KCC2 expression ratio is associated with several brain disorders. Preclinical/clinical studies have shown that NKCC1 inhibition by the United States FDA-approved diuretic bumetanide is a potential therapeutic strategy in preclinical/clinical studies of multiple neurological conditions. However, bumetanide has poor brain penetration and causes unwanted diuresis by inhibiting NKCC2 in the kidney. To overcome these issues, a growing number of studies have reported more brain-penetrating and/or selective bumetanide prodrugs, analogs, and new molecular entities. Here, we review the evidence for NKCC1 pharmacological inhibition as an effective strategy to manage neurological disorders. We also discuss the advantages and limitations of bumetanide repurposing and the benefits and risks of new NKCC1 inhibitors as therapeutic agents for brain disorders.
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Affiliation(s)
- Annalisa Savardi
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy; Dulbecco Telethon Institute, 00185 Rome, Italy; Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Marco Borgogno
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Marco De Vivo
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.
| | - Laura Cancedda
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy; Dulbecco Telethon Institute, 00185 Rome, Italy.
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21
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Chen S, Lee J, Truong TM, Alhassen S, Baldi P, Alachkar A. Age-Related Neurometabolomic Signature of Mouse Brain. ACS Chem Neurosci 2021; 12:2887-2902. [PMID: 34283556 DOI: 10.1021/acschemneuro.1c00259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Neurometabolites are the ultimate gene products in the brain and the most precise biomolecular indicators of brain endophenotypes. Metabolomics is the only "omics" that provides a moment-to-moment "snapshot" of brain circuits' biochemical activities in response to external stimuli within the context of specific genetic variations. Although the expression levels of neurometabolites are highly dynamic, the underlying metabolic processes are tightly regulated during brain development, maturation, and aging. Therefore, this study aimed to identify mouse brain metabolic profiles in neonatal and adult stages and reconstruct both the active metabolic network and the metabolic pathway functioning. Using high-throughput metabolomics and bioinformatics analyses, we show that the neonatal mouse brain has its distinct metabolomic signature, which differs from the adult brain. Furthermore, lipid metabolites showed the most profound changes between the neonatal and adult brain, with some lipid species reaching 1000-fold changes. There were trends of age-dependent increases and decreases among lipids and non-lipid metabolites, respectively. A few lipid metabolites such as HexCers and SHexCers were almost absent in neonatal brains, whereas other non-lipid metabolites such as homoarginine were absent in the adult brains. Several molecules that act as neurotransmitters/neuromodulators showed age-dependent levels, with adenosine and GABA exhibiting around 100- and 10-fold increases in the adult compared with the neonatal brain. Of particular interest is the observation that purine and pyrimidines nucleobases exhibited opposite age-dependent changes. Bioinformatics analysis revealed an enrichment of lipid biosynthesis pathways in metabolites, whose levels increased in adult brains. In contrast, pathways involved in the metabolism of amino acids, nucleobases, glucose (glycolysis), tricarboxylic acid cycle (TCA) were enriched in metabolites whose levels were higher in the neonatal brains. Many of these pathways are associated with pathological conditions, which can be predicted as early as the neonatal stage. Our study provides an initial age-related biochemical directory of the mouse brain and warrants further studies to identify temporal brain metabolome across the lifespan, particularly during adolescence and aging. Such neurometabolomic data may provide important insight about the onset and progression of neurological/psychiatric disorders and may ultimately lead to the development of precise diagnostic biomarkers and more effective preventive/therapeutic strategies.
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Affiliation(s)
- Siwei Chen
- Department of Computer Science, School of Information and Computer Sciences, University of California—Irvine, Irvine, California 92697, United States
- Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California—Irvine, Irvine, California 92697, United States
| | - Justine Lee
- Department of Pharmaceutical Sciences, School of Pharmacy, University of California—Irvine, Irvine, California 92697, United States
| | - Tri Minh Truong
- Department of Pharmaceutical Sciences, School of Pharmacy, University of California—Irvine, Irvine, California 92697, United States
| | - Sammy Alhassen
- Department of Pharmaceutical Sciences, School of Pharmacy, University of California—Irvine, Irvine, California 92697, United States
| | - Pierre Baldi
- Department of Computer Science, School of Information and Computer Sciences, University of California—Irvine, Irvine, California 92697, United States
- Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California—Irvine, Irvine, California 92697, United States
| | - Amal Alachkar
- Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California—Irvine, Irvine, California 92697, United States
- Department of Pharmaceutical Sciences, School of Pharmacy, University of California—Irvine, Irvine, California 92697, United States
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22
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Percelay S, Freret T, Turnbull N, Bouet V, Boulouard M. Combination of MAP6 deficit, maternal separation and MK801 in female mice: A 3-hit animal model of neurodevelopmental disorder with cognitive deficits. Behav Brain Res 2021; 413:113473. [PMID: 34280461 DOI: 10.1016/j.bbr.2021.113473] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 07/08/2021] [Accepted: 07/14/2021] [Indexed: 11/26/2022]
Abstract
Schizophrenia is a major psychiatric disease still lacking efficient treatment, particularly for cognitive deficits. To go further in research of new treatments that would encompass all the symptoms associated with this pathology, preclinical animal models need to be improved. To date, the aetiology of schizophrenia is unknown, but there is increasing evidence to highlight its multifactorial nature. We built a new neurodevelopmental mouse model gathering a triple factor combination (3-M): a genetic factor (partial deletion of MAP6 gene), an early stress (maternal separation) and a late pharmacological factor (MK801 administration, 0.05 mg/kg, i.p., daily for 5 days). The effects of each factor and of their combination were investigated on several behaviours including cognitive functions. While each individual factor induced slight deficits in one or another behavioural test, 3-M conditioning induces a wider phenotype with hyperlocomotion and cognitive deficits (working memory and social recognition). This study confirms the hypothesis that genetic, environmental and pharmacological factors, even if not deleterious by themselves, could act synergistically to induce a deleterious behavioural phenotype. It moreover encourages the use of such combined models to improve translational research on neurodevelopmental disorders.
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Affiliation(s)
- Solenn Percelay
- Normandie Université, UNICAEN, INSERM, COMETE, CYCERON, CHU Caen, 14000, Caen, France.
| | - Thomas Freret
- Normandie Université, UNICAEN, INSERM, COMETE, CYCERON, CHU Caen, 14000, Caen, France
| | - Nicole Turnbull
- Normandie Université, UNICAEN, INSERM, COMETE, CYCERON, CHU Caen, 14000, Caen, France
| | - Valentine Bouet
- Normandie Université, UNICAEN, INSERM, COMETE, CYCERON, CHU Caen, 14000, Caen, France
| | - Michel Boulouard
- Normandie Université, UNICAEN, INSERM, COMETE, CYCERON, CHU Caen, 14000, Caen, France
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23
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Igarashi K, Kuchiiwa T, Kuchiiwa S, Iwai H, Tomita K, Sato T. Kamishoyosan (a Japanese traditional herbal formula), which effectively reduces the aggressive biting behavior of male and female mice, and potential regulation through increase of Tph1, Tph2, and Esr2 mRNA levels. Brain Res 2021; 1768:147580. [PMID: 34260963 DOI: 10.1016/j.brainres.2021.147580] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/23/2021] [Accepted: 07/06/2021] [Indexed: 01/29/2023]
Abstract
Kamishoyosan (KSS), a Japanese traditional herbal formula, is used to treat symptoms related to the autonomic nervous system in men and women; it is especially known for improving the symptoms of irritability (e.g., bad temper and persistent anger). Although clinical and ethological studies of KSS have been conducted, its efficacy in reducing irritability remains to be validated. In the present study, male and female ddY-strain mice were isolation-reared for 8 weeks (from the third postnatal week) to induce pathologically aggressive biting behavior (ABB), which was used as an indicator of irritability. The ABB of mice toward metal rods was measured using the Aggressive Response Meter. An intraperitoneal administration of KSS (100 mg/kg) effectively reduced ABB in male and female mice at 2 h after the administration; however, this effect was canceled by prior administration of WAY-100635 [a 5-hydroxytryptoamine (5-HT)-1A receptor antagonist; 0.5 mg/kg] and bicuculline (a type-A gamma-aminobutyric acid receptor antagonist; 1.0 mg/kg). Additionally, tamoxifen, ICI-182780, and G-15 (all estrogen receptor antagonists) inhibited the action of KSS in a dose-dependent manner. Furthermore, gene expression of tryptophan hydroxylase (Tph) 1 and Tph2 were increased and 5-HT immunofluorescence was slightly increased in the dorsal raphe nucleus (DRN) of isolation-reared mice administered with KSS. Collectively, these results indicate that KSS effectively reduces ABB in isolation-reared male and female mice through stimulation of 5-HT production in the DRN. Our findings also suggest that gene expression of estrogen receptor (Esr) 2 increased in the DRN might be associated with the reduction of ABB.
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Affiliation(s)
- Kento Igarashi
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Toshiko Kuchiiwa
- Department of Clinical Psychology, Graduate School of Human Science, Kagoshima Immaculate Herat University, 2365 Amatatsu-Cho, Satsuma-Sendai 895-0011, Japan; Department of Morphological Science, Field of Neurology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Satoshi Kuchiiwa
- Department of Morphological Science, Field of Neurology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Haruki Iwai
- Department of Oral Anatomy and Cell Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Kazuo Tomita
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Tomoaki Sato
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
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24
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Martynyuk AE, Ju LS, Morey TE. The potential role of stress and sex steroids in heritable effects of sevoflurane. Biol Reprod 2021; 105:735-746. [PMID: 34192761 DOI: 10.1093/biolre/ioab129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/17/2021] [Accepted: 06/25/2021] [Indexed: 12/11/2022] Open
Abstract
Most surgical procedures require general anesthesia, which is a reversible deep sedation state lacking all perception. The induction of this state is possible because of complex molecular and neuronal network actions of general anesthetics (GAs) and other pharmacological agents. Laboratory and clinical studies indicate that the effects of GAs may not be completely reversible upon anesthesia withdrawal. The long-term neurocognitive effects of GAs, especially when administered at the extremes of ages, are an increasingly recognized health concern and the subject of extensive laboratory and clinical research. Initial studies in rodents suggest that the adverse effects of GAs, whose actions involve enhancement of GABA type A receptor activity (GABAergic GAs), can also extend to future unexposed offspring. Importantly, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, covering nearly all age groups that may have children after exposure to anesthesia. More studies are needed to understand when and how the clinical use of GAs in a large and growing population of patients can result in lower resilience to diseases in the even larger population of their unexposed offspring. This minireview is focused on the authors' published results and data in the literature supporting the notion that GABAergic GAs, in particular sevoflurane, may upregulate systemic levels of stress and sex steroids and alter expressions of genes that are essential for the functioning of these steroid systems. The authors hypothesize that stress and sex steroids are involved in the mediation of sex-specific heritable effects of sevoflurane.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA.,McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
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25
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Gozel O, Gerstner W. A functional model of adult dentate gyrus neurogenesis. eLife 2021; 10:66463. [PMID: 34137370 PMCID: PMC8260225 DOI: 10.7554/elife.66463] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 06/16/2021] [Indexed: 12/27/2022] Open
Abstract
In adult dentate gyrus neurogenesis, the link between maturation of newborn neurons and their function, such as behavioral pattern separation, has remained puzzling. By analyzing a theoretical model, we show that the switch from excitation to inhibition of the GABAergic input onto maturing newborn cells is crucial for their proper functional integration. When the GABAergic input is excitatory, cooperativity drives the growth of synapses such that newborn cells become sensitive to stimuli similar to those that activate mature cells. When GABAergic input switches to inhibitory, competition pushes the configuration of synapses onto newborn cells toward stimuli that are different from previously stored ones. This enables the maturing newborn cells to code for concepts that are novel, yet similar to familiar ones. Our theory of newborn cell maturation explains both how adult-born dentate granule cells integrate into the preexisting network and why they promote separation of similar but not distinct patterns.
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Affiliation(s)
- Olivia Gozel
- School of Life Sciences and School of Computer and Communication Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Departments of Neurobiology and Statistics, University of Chicago, Chicago, United States.,Grossman Center for Quantitative Biology and Human Behavior, University of Chicago, Chicago, United States
| | - Wulfram Gerstner
- School of Life Sciences and School of Computer and Communication Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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26
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Blair LM, Ford JL, Gugiu PC, Pickler RH, Munro CL, Anderson CM. Prediction of Cognitive Ability With Social Determinants in Children of Low Birth Weight. Nurs Res 2021; 69:427-435. [PMID: 33141526 PMCID: PMC8926395 DOI: 10.1097/nnr.0000000000000438] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Despite strong prevention efforts and advances in neonatal care in recent decades, low birth weight remains a serious public health problem in the United States, and survivors remain at increased risk for lifelong problems including cognitive deficits. Current regional and local strategies for referral often rely on variable thresholds for birth weight and gestational age that may be poor analogues to cognitive risk. Improving early referral criteria offers many benefits, including improved cognitive outcomes for children and improved cost-effectiveness and resource utilization in resource-limited communities. OBJECTIVES We hypothesized that social determinants measurable at birth or at birth hospital discharge, when combined with birth weight and gestational age, would offer an improvement over birth weight and gestational age alone in predicting cognitive test scores in school-aged children with low birth weight. METHODS We conducted a secondary analysis using a birth cohort of children from the Fragile Families and Child Wellbeing Study. We created a panel of maternal, familial, and community-level social determinant indicators from the data and examined associations with cognitive measures assessed at age of 9 years. RESULTS The final social determinant model was statistically significant and explained 35% of the total variance in composite test scores. The "standard care" model (birth weight and gestational age) only explained 9% of the variance. DISCUSSION Assessment of social determinants may offer improvement over traditional referral criteria to identify children most at risk of cognitive deficits after low birth weight.
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Affiliation(s)
- Lisa M Blair
- Lisa M. Blair, PhD, RNC-NIC, is Postdoctoral Scholar, Perinatal Research and Wellness Center, University of Kentucky College of Nursing, Lexington. Jodi L. Ford, PhD, RN, is Associate Professor, The Ohio State University College of Nursing, Columbus. P. Cristian Gugiu, PhD, was Assistant Professor, The Ohio State University College of Education and Human Ecology, Columbus, at the time of the study completion and is now in private practice. Rita H. Pickler, PhD, RN, FAAN, is FloAnn Sours Easton Endowed Professor of Child and Adolescent Health and Director of PhD and MS in Nursing Science Programs, The Ohio State University College of Nursing, Columbus. Cindy Munro, PhD, ANP-BC, FAAN, FAANP, FAAAS, is Dean and Professor, University of Miami School of Nursing and Health Studies, Coral Gables. Cindy M. Anderson, PhD, APRN-CNP, ANEF, FAHA, FNAP, FAAN, is Senior Associate Dean for Academic Affairs and Educational Innovation and Professor, The Ohio State University College of Nursing, Columbus
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27
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Peerboom C, Wierenga CJ. The postnatal GABA shift: A developmental perspective. Neurosci Biobehav Rev 2021; 124:179-192. [PMID: 33549742 DOI: 10.1016/j.neubiorev.2021.01.024] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 01/13/2021] [Accepted: 01/28/2021] [Indexed: 12/13/2022]
Abstract
GABA is the major inhibitory neurotransmitter that counterbalances excitation in the mature brain. The inhibitory action of GABA relies on the inflow of chloride ions (Cl-), which hyperpolarizes the neuron. In early development, GABA signaling induces outward Cl- currents and is depolarizing. The postnatal shift from depolarizing to hyperpolarizing GABA is a pivotal event in brain development and its timing affects brain function throughout life. Altered timing of the postnatal GABA shift is associated with several neurodevelopmental disorders. Here, we argue that the postnatal shift from depolarizing to hyperpolarizing GABA represents the final shift in a sequence of GABA shifts, regulating proliferation, migration, differentiation, and finally plasticity of developing neurons. Each developmental GABA shift ensures that the instructive role of GABA matches the circumstances of the developing network. Sensory input may be a crucial factor in determining proper timing of the postnatal GABA shift. A developmental perspective is necessary to interpret the full consequences of a mismatch between connectivity, activity and GABA signaling during brain development.
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Affiliation(s)
- Carlijn Peerboom
- Cell Biology, Neurobiology and Biophysics, Biology Department, Faculty of Science, Utrecht University, 3584 CH, Utrecht, the Netherlands
| | - Corette J Wierenga
- Cell Biology, Neurobiology and Biophysics, Biology Department, Faculty of Science, Utrecht University, 3584 CH, Utrecht, the Netherlands.
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28
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Gazzo G, Melchior M, Caussaint A, Gieré C, Lelièvre V, Poisbeau P. Overexpression of chloride importer NKCC1 contributes to the sensory-affective and sociability phenotype of rats following neonatal maternal separation. Brain Behav Immun 2021; 92:193-202. [PMID: 33316378 DOI: 10.1016/j.bbi.2020.12.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Early life stress is known to affect the development of the nervous system and its function at a later age. It increases the risk to develop psychiatric disorders as well as chronic pain and its associated affective comorbidities across the lifespan. GABAergic inhibition is important for the regulation of central function and related behaviors, including nociception, anxiety or social interactions, and requires low intracellular chloride levels. Of particular interest, the oxytocinergic (OTergic) system exerts potent anxiolytic, analgesic and pro-social properties and is known to be involved in the regulation of chloride homeostasis and to be impaired following early life stress. METHODS We used behavioral measures to evaluate anxiety, social interactions and pain responses in a rat model of neonatal maternal separation (NMS). Using quantitative PCR, we investigated whether NMS was associated with alterations in the expression of chloride transporters in the cerebrum and spinal cord. Finally, we evaluated the contribution of OTergic signaling and neuro-inflammatory processes in the observed phenotype. RESULTS NMS animals displayed a long-lasting upregulation of chloride importer Na-K-Cl cotransporter type 1 (NKCC1) expression in the cerebrum and spinal cord. Neonatal administration of the NKCC1 inhibitor bumetanide or oxytocin successfully normalized the anxiety-like symptoms and the lack of social preference observed in NMS animals. Phenotypic alterations were associated with a pro-inflammatory state which could contribute to NKCC1 upregulation. CONCLUSIONS This work suggests that an impaired chloride homeostasis, linked to oxytocin signaling dysfunction and to neuro-inflammatory processes, could contribute to the sensori-affective phenotype following NMS.
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Affiliation(s)
- Géraldine Gazzo
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France
| | - Meggane Melchior
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France
| | - Andréa Caussaint
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France
| | - Clémence Gieré
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France
| | - Vincent Lelièvre
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France
| | - Pierrick Poisbeau
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France.
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29
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Age-dependent shift in spontaneous excitation-inhibition balance of infralimbic prefrontal layer II/III neurons is accelerated by early life stress, independent of forebrain mineralocorticoid receptor expression. Neuropharmacology 2020; 180:108294. [PMID: 32882227 DOI: 10.1016/j.neuropharm.2020.108294] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/20/2020] [Accepted: 08/29/2020] [Indexed: 02/05/2023]
Abstract
In this study we tested the hypothesis i) that age-dependent shifts in the excitation-inhibition balance of prefrontal neurons are accelerated by early life stress, a risk factor for the etiology of many psychiatric disorders; and if so, ii) that this process is exacerbated by genetic forebrain-specific downregulation of the mineralocorticoid receptor, a receptor that was earlier found to be a protective factor for negative effects of early life stress in both rodents and humans. In agreement with the literature, an age-dependent downregulation of the excitation-inhibition balance was found both with regard to spontaneous and evoked synaptic currents. The age-dependent shift in spontaneous excitatory relative to inhibitory currents was significantly accelerated by early life stress, but this was not exacerbated by reduction in mineralocorticoid receptor expression. The age-dependent changes in the excitation-inhibition balance were mirrored by similar changes in receptor subunit expression and morphological alterations, particularly in spine density, which could thus potentially contribute to the functional changes. However, none of these parameters displayed acceleration by early life stress, nor depended on mineralocorticoid receptor expression. We conclude that, in agreement with the hypothesis, early life stress accelerates the developmental shift of the excitation-inhibition balance but, contrary to expectation, there is no evidence for a putative protective role of the mineralocorticoid receptor in this system. In view of the modest effect of early life stress on the excitation-inhibition balance, alternative mechanisms potentially underlying the development of psychiatric disorders should be further explored.
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30
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Environmental regulation of the chloride transporter KCC2: switching inflammation off to switch the GABA on? Transl Psychiatry 2020; 10:349. [PMID: 33060559 PMCID: PMC7562743 DOI: 10.1038/s41398-020-01027-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 09/08/2020] [Accepted: 09/14/2020] [Indexed: 12/15/2022] Open
Abstract
Chloride homeostasis, the main determinant factor for the dynamic tuning of GABAergic inhibition during development, has emerged as a key element altered in a wide variety of brain disorders. Accordingly, developmental disorders such as schizophrenia, Autism Spectrum Disorder, Down syndrome, epilepsy, and tuberous sclerosis complex (TSC) have been associated with alterations in the expression of genes codifying for either of the two cotransporters involved in the excitatory-to-inhibitory GABA switch, KCC2 and NKCC1. These alterations can result from environmental insults, including prenatal stress and maternal separation which share, as common molecular denominator, the elevation of pro-inflammatory cytokines. In this review we report and systemize recent research articles indicating that different perinatal environmental perturbations affect the expression of chloride transporters, delaying the developmental switch of GABA signaling, and that inflammatory cytokines, in particular interleukin 1β, may represent a key causal factor for this phenomenon. Based on literature data, we provide therefore a unifying conceptual framework, linking environmental hits with the excitatory-to-inhibitory GABA switch in the context of brain developmental disorders.
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31
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Lin Y, Lei L, Ju LS, Xu N, Morey TE, Gravenstein N, Yang J, Martynyuk AE. Neonatal exposure to sevoflurane expands the window of vulnerability to adverse effects of subsequent exposure to sevoflurane and alters hippocampal morphology via decitabine-sensitive mechanisms. Neurosci Lett 2020; 735:135240. [PMID: 32650051 DOI: 10.1016/j.neulet.2020.135240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/09/2020] [Accepted: 07/07/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Deficiencies in neurocognitive function have been found in late childhood or adolescence in patients who had prolonged and/or repeated early-life general anesthesia. Animal studies suggest that anesthetic-induced impairment in the neuron-specific K+-2Cl- (Kcc2) Cl- exporter expression, which regulates developmental maturation of GABA type A receptor (GABAAR) signaling from excitatory to inhibitory, may play a mediating role. We tested whether the DNA methyltransferase (DNMT) inhibitor decitabine ameliorates the anesthetic's adverse effects. METHODS Sprague-Dawley male rats were injected with vehicle or decitabine 30 min before 2.1 % sevoflurane exposure for 5 h on postnatal day 5 (P5). On P19, P20, or P21, electroencephalography-detectable seizures were measured during 1 h of sevoflurane exposure, followed by collection of the trunk blood and brain tissue samples. Other rats were evaluated for changes in hippocampal CA1 dendrite morphology and gene expressions on ≥ P120. RESULTS Rats in the vehicle plus sevoflurane group responded to sevoflurane exposure on P19, P20 or P21 with electroencephalography-detectable seizures and stress-like corticosterone secretion and had altered hippocampal dendrite morphology in adulthood. These rats had expressions of Kcc2 and Dnmt genes downregulated and upregulated, respectively, in the P19 - P21 cortex and hypothalamus and the ≥ P120 hippocampus. All measured parameters in the sevoflurane-exposed rats that were pretreated with decitabine were not different from those in the control group. CONCLUSIONS Neonatal exposure to sevoflurane sensitizes rats to adverse effects of repeated exposure to the anesthetic. The anesthetic-caused changes in the decitabine-sensitive mechanisms may play a mediating role in the developmental effects of early-life anesthesia.
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Affiliation(s)
- Yunan Lin
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Lei Lei
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Ning Xu
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jianjun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States.
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Martynyuk AE, Ju LS, Morey TE, Zhang JQ. Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics. World J Psychiatry 2020; 10:81-94. [PMID: 32477904 PMCID: PMC7243620 DOI: 10.5498/wjp.v10.i5.81] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/18/2020] [Accepted: 03/26/2020] [Indexed: 02/05/2023] Open
Abstract
The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jia-Qiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
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Human Pluripotent Stem Cell-Derived Neurons Are Functionally Mature In Vitro and Integrate into the Mouse Striatum Following Transplantation. Mol Neurobiol 2020; 57:2766-2798. [PMID: 32356172 PMCID: PMC7253531 DOI: 10.1007/s12035-020-01907-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 03/23/2020] [Indexed: 01/23/2023]
Abstract
Human pluripotent stem cells (hPSCs) are a powerful tool for modelling human development. In recent years, hPSCs have become central in cell-based therapies for neurodegenerative diseases given their potential to replace affected neurons. However, directing hPSCs into specific neuronal types is complex and requires an accurate protocol that mimics endogenous neuronal development. Here we describe step-by-step a fast feeder-free neuronal differentiation protocol to direct hPSCs to mature forebrain neurons in 37 days in vitro (DIV). The protocol is based upon a combination of specific morphogens, trophic and growth factors, ions, neurotransmitters and extracellular matrix elements. A human-induced PSC line (Ctr-Q33) and a human embryonic stem cell line (GEN-Q18) were used to reinforce the potential of the protocol. Neuronal activity was analysed by single-cell calcium imaging. At 8 DIV, we obtained a homogeneous population of hPSC-derived neuroectodermal progenitors which self-arranged in bi-dimensional neural tube-like structures. At 16 DIV, we generated hPSC-derived neural progenitor cells (NPCs) with mostly a subpallial identity along with a subpopulation of pallial NPCs. Terminal in vitro neuronal differentiation was confirmed by the expression of microtubule associated protein 2b (Map 2b) by almost 100% of hPSC-derived neurons and the expression of specific-striatal neuronal markers including GABA, CTIP2 and DARPP-32. HPSC-derived neurons showed mature and functional phenotypes as they expressed synaptic markers, voltage-gated ion channels and neurotransmitter receptors. Neurons displayed diverse spontaneous activity patterns that were classified into three major groups, namely “high”, “intermediate” and “low” firing neurons. Finally, transplantation experiments showed that the NPCs survived and differentiated within mouse striatum for at least 3 months. NPCs integrated host environmental cues and differentiated into striatal medium-sized spiny neurons (MSNs), which successfully integrated into the endogenous circuitry without teratoma formation. Altogether, these findings demonstrate the potential of this robust human neuronal differentiation protocol, which will bring new opportunities for the study of human neurodevelopment and neurodegeneration, and will open new avenues in cell-based therapies, pharmacological studies and alternative in vitro toxicology.
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Scheyer AF, Borsoi M, Wager-Miller J, Pelissier-Alicot AL, Murphy MN, Mackie K, Manzoni OJJ. Cannabinoid Exposure via Lactation in Rats Disrupts Perinatal Programming of the Gamma-Aminobutyric Acid Trajectory and Select Early-Life Behaviors. Biol Psychiatry 2020; 87:666-677. [PMID: 31653479 PMCID: PMC7056509 DOI: 10.1016/j.biopsych.2019.08.023] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 08/26/2019] [Accepted: 08/26/2019] [Indexed: 01/22/2023]
Abstract
BACKGROUND Cannabis usage is increasing with its widespread legalization. Cannabis use by mothers during lactation transfers active cannabinoids to the developing offspring during this critical period and alters postnatal neurodevelopment. A key neurodevelopmental landmark is the excitatory to inhibitory gamma-aminobutyric acid (GABA) switch caused by reciprocal changes in expression ratios of the K+/Cl- transporters potassium-chloride cotransporter 2 (KCC2) and sodium-potassium-chloride transporter (NKCC1). METHODS Rat dams were treated with Δ9-tetrahydrocannabinol or a synthetic cannabinoid during the first 10 days of postnatal development, and experiments were then conducted in the offspring exposed to these drugs via lactation. The network influence of GABA transmission was analyzed using cell-attached recordings. KCC2 and NKCC1 levels were determined using Western blot and quantitative polymerase chain reaction analyses. Ultrasonic vocalization and homing behavioral experiments were carried out at relevant time points. RESULTS Treating rat dams with cannabinoids during early lactation retards transcriptional upregulation and expression of KCC2, thereby delaying the GABA switch in pups of both sexes. This perturbed trajectory was corrected by the NKCC1 antagonist bumetanide and accompanied by alterations in ultrasonic vocalization without changes in homing behavior. Neurobehavioral deficits were prevented by CB1 receptor antagonism during maternal exposure, showing that the CB1 receptor underlies the cannabinoid-induced alterations. CONCLUSIONS These results reveal how perinatal cannabinoid exposure retards an early milestone of development, delaying the trajectory of GABA's polarity transition and altering early-life communication.
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Affiliation(s)
- Andrew F Scheyer
- Institut de neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale U1249, Marseille, France; Aix-Marseille University, Marseille, France; Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, Institut National de la Santé et de la Recherche Médicale-Aix-Marseille University/Indiana University
| | - Milene Borsoi
- Institut de neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale U1249, Marseille, France; Aix-Marseille University, Marseille, France; Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, Institut National de la Santé et de la Recherche Médicale-Aix-Marseille University/Indiana University
| | - Jim Wager-Miller
- Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, Institut National de la Santé et de la Recherche Médicale-Aix-Marseille University/Indiana University; Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana
| | - Anne-Laure Pelissier-Alicot
- Institut de neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale U1249, Marseille, France; Aix-Marseille University, Marseille, France; Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, Institut National de la Santé et de la Recherche Médicale-Aix-Marseille University/Indiana University; Service de Psychiatrie, CHU Conception, Assistance Publique - Hôpitaux de Marseille, Marseille, France; Service de Médecine Légale, CHU Timone-Adultes, Assistance Publique - Hôpitaux de Marseille, Marseille, France
| | - Michelle N Murphy
- Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, Institut National de la Santé et de la Recherche Médicale-Aix-Marseille University/Indiana University; Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana
| | - Ken Mackie
- Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, Institut National de la Santé et de la Recherche Médicale-Aix-Marseille University/Indiana University; Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.
| | - Olivier J J Manzoni
- Institut de neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale U1249, Marseille, France; Aix-Marseille University, Marseille, France; Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, Institut National de la Santé et de la Recherche Médicale-Aix-Marseille University/Indiana University.
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Semple BD, Dill LK, O'Brien TJ. Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis? Front Pharmacol 2020; 11:2. [PMID: 32116690 PMCID: PMC7010861 DOI: 10.3389/fphar.2020.00002] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 01/03/2020] [Indexed: 12/16/2022] Open
Abstract
The development of epilepsy, a process known as epileptogenesis, often occurs later in life following a prenatal or early postnatal insult such as cerebral ischemia, stroke, brain trauma, or infection. These insults share common pathophysiological pathways involving innate immune activation including neuroinflammation, which is proposed to play a critical role in epileptogenesis. This review provides a comprehensive overview of the latest preclinical evidence demonstrating that early life immune challenges influence neuronal hyperexcitability and predispose an individual to later life epilepsy. Here, we consider the range of brain insults that may promote the onset of chronic recurrent spontaneous seizures at adulthood, spanning intrauterine insults (e.g. maternal immune activation), perinatal injuries (e.g. hypoxic–ischemic injury, perinatal stroke), and insults sustained during early postnatal life—such as fever-induced febrile seizures, traumatic brain injuries, infections, and environmental stressors. Importantly, all of these insults represent, to some extent, an immune challenge, triggering innate immune activation and implicating both central and systemic inflammation as drivers of epileptogenesis. Increasing evidence suggests that pro-inflammatory cytokines such as interleukin-1 and subsequent signaling pathways are important mediators of seizure onset and recurrence, as well as neuronal network plasticity changes in this context. Our current understanding of how early life immune challenges prime microglia and astrocytes will be explored, as well as how developmental age is a critical determinant of seizure susceptibility. Finally, we will consider the paradoxical phenomenon of preconditioning, whereby these same insults may conversely provide neuroprotection. Together, an improved appreciation of the neuroinflammatory mechanisms underlying the long-term epilepsy risk following early life insults may provide insight into opportunities to develop novel immunological anti-epileptogenic therapeutic strategies.
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Affiliation(s)
- Bridgette D Semple
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.,Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.,Department of Neurology, Alfred Health, Melbourne, VIC, Australia
| | - Larissa K Dill
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.,Department of Neurology, Alfred Health, Melbourne, VIC, Australia
| | - Terence J O'Brien
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.,Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.,Department of Neurology, Alfred Health, Melbourne, VIC, Australia
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Kiernan MC, Ziemann U, Eisen A. Amyotrophic lateral sclerosis: Origins traced to impaired balance between neural excitation and inhibition in the neonatal period. Muscle Nerve 2019; 60:232-235. [PMID: 31233613 DOI: 10.1002/mus.26617] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 06/17/2019] [Accepted: 06/18/2019] [Indexed: 12/14/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is an adult onset disease but with an increasingly recognized preclinical prodrome. A wide spectrum of investigative approaches has identified loss of inhibitory function at the heart of ALS. In developing an explanation for the onset of ALS, it remains a consideration that ALS has its origins in neonatal derangement of the γ-aminobutyric acid (GABA)-ergic system, with delayed conversion from excitatory to mature inhibitory GABA and impaired excitation/inhibition balance. If this is so, the resulting chronic excitotoxicity could marginalize cortical network functioning very early in life, laying the path for neurodegeneration. The possibility that adult-onset neurodegenerative conditions might have their roots in early developmental derangements is worthy of consideration, particularly in relation to current models of disease pathogenesis. Unraveling the very early molecular events will be crucial in developing a better understanding of ALS and other adult neurodegenerative disorders. Muscle Nerve, 2019.
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Affiliation(s)
- Matthew C Kiernan
- The University of Sydney School of Medicine Brain and Mind Centre, Building F, Level 4, 94 Mallett Street, Camperdown, New South Wales, 2050, Australia
- Department of Neurology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Ulf Ziemann
- Department of Neurology & Stroke, and Hertie-Institute for clinical brain research, University of Tübingen, Tübingen, Germany
| | - Andrew Eisen
- Division of Neurology (Emeritus), Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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Abstract
The developmental period constitutes a critical window of sensitivity to stress. Indeed, early-life adversity increases the risk to develop psychiatric diseases, but also gastrointestinal disorders such as the irritable bowel syndrome at adulthood. In the past decade, there has been huge interest in the gut-brain axis, especially as regards stress-related emotional behaviours. Animal models of early-life adversity, in particular, maternal separation (MS) in rodents, demonstrate lasting deleterious effects on both the gut and the brain. Here, we review the effects of MS on both systems with a focus on stress-related behaviours. In addition, we discuss more recent findings showing the impact of gut-directed interventions, including nutrition with pre- and probiotics, illustrating the role played by gut microbiota in mediating the long-term effects of MS. Overall, preclinical studies suggest that nutritional approaches with pro- and prebiotics may constitute safe and efficient strategies to attenuate the effects of early-life stress on the gut-brain axis. Further research is required to understand the complex mechanisms underlying gut-brain interaction dysfunctions after early-life stress as well as to determine the beneficial impact of gut-directed strategies in a context of early-life adversity in human subjects.
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Braren SH, Perry RE, Ursache A, Blair C. Socioeconomic risk moderates the association between caregiver cortisol levels and infant cortisol reactivity to emotion induction at 24 months. Dev Psychobiol 2019; 61:573-591. [PMID: 30820941 PMCID: PMC6488391 DOI: 10.1002/dev.21832] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 01/09/2019] [Accepted: 01/11/2019] [Indexed: 01/09/2023]
Abstract
Relations between maternal baseline cortisol and infant cortisol reactivity to an emotion induction procedure at child ages 7, 15, and 24 months were analyzed using data from the Family Life Project (N = 1,292). The emotion induction consisted of a series of standardized and validated tasks, including an arm restraint, toy removal, and mask presentation, intended to elicit responses of fear and frustration. Results revealed that at 7 and 15 months, maternal baseline cortisol was negatively related to child cortisol reactivity, such that children of mothers with lower cortisol exhibited steeper cortisol increases in response to the emotion induction. At 24 months, the association between mother and infant cortisol was moderated by socioeconomic risk, such that maternal baseline cortisol was associated with child cortisol reactivity only in dyads characterized by low socioeconomic risk. Furthermore, at 24 months, children of mothers with low baseline cortisol and low socioeconomic risk exhibited decreasing cortisol responses, whereas children of mothers with low baseline cortisol but high risk exhibited flat cortisol responses. Children in dyads characterized by high baseline maternal cortisol also exhibited flat cortisol responses regardless of socioeconomic risk. The role of caregiver physiology in the regulation of the child's stress response in the context of adversity is discussed.
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Affiliation(s)
- Stephen H. Braren
- Department of Applied Psychology, 246 Greene Street, Kimball Hall, 8 Floor, New York University, New York, NY, 10012, United States
| | - Rosemarie E. Perry
- Department of Applied Psychology, 246 Greene Street, Kimball Hall, 8 Floor, New York University, New York, NY, 10012, United States
| | - Alexandra Ursache
- Department of Population Health, 227 East 30th Street, 7 Floor, New York University School of Medicine, New York, NY, 10016, United States
| | - Clancy Blair
- Department of Applied Psychology, 246 Greene Street, Kimball Hall, 8 Floor, New York University, New York, NY, 10012, United States
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Mohamad FH, Has ATC. The α5-Containing GABA A Receptors-a Brief Summary. J Mol Neurosci 2019; 67:343-351. [PMID: 30607899 DOI: 10.1007/s12031-018-1246-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 12/17/2018] [Indexed: 12/21/2022]
Abstract
GABAA receptors are the major inhibitory neurotransmitter receptor in the human brain. The receptors are assembled from combination of protein subunits in pentameric complex which may consist of α1-6, β1-3, γ1-3, ρ1-3, δ, ε, θ, or π subunits. There are a theoretical > 150,000 possible assemblies and arrangements of GABAA subunits, although only a few combinations have been found in human with the most dominant consists of 2α1, 2β2, and 1γ2 in a counterclockwise arrangement as seen from the synaptic cleft. The receptors also possess binding sites for various unrelated substances including benzodiazepines, barbiturates, and anesthetics. The α5-containing GABAARs only make up ≤ 5% of the entire receptor population, but up to 25% of the receptor subtype is located in the crucial learning and memory-associated area of the brain-the hippocampus, which has ignited myriads of hypotheses and theories in regard to its role. As well as exhibiting synaptic phasic inhibition, the α5-containing receptors are also extrasynaptic and mediate tonic inhibition with continuously occurring smaller amplitude. Studies on negative-allosteric modulators for reducing this tonic inhibition have been shown to enhance learning and memory in neurological disorders such as schizophrenia, Down syndrome, and autism with a possible alternative benzodiazepine binding site. Therefore, a few α5 subunit-specific compounds have been developed to address these pharmacological needs. With its small population, the α5-containing receptors could be the key and also the answer for many untreated cognitive dysfunctions and disorders.
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Affiliation(s)
- Fatin H Mohamad
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kampus Kesihatan, 16150, Kubang Kerian, Kelantan, Malaysia
| | - Ahmad Tarmizi Che Has
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kampus Kesihatan, 16150, Kubang Kerian, Kelantan, Malaysia.
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Song ZJ, Yang SJ, Han L, Wang B, Zhu G. Postnatal calpeptin treatment causes hippocampal neurodevelopmental defects in neonatal rats. Neural Regen Res 2019; 14:834-840. [PMID: 30688269 PMCID: PMC6375038 DOI: 10.4103/1673-5374.249231] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Our previous studies showed that the early use of calpain inhibitors reduces calpain activity in multiple brain regions, and that postnatal treatment with calpeptin may lead to cerebellar motor dysfunction. However, it remains unclear whether postnatal calpeptin application affects hippocampus-related behaviors. In this study, Sprague-Dawley rats were purchased from the Animal Center of Anhui Medical University of China. For the experiments in the adult stage, rats were intraperitoneally injected with calpeptin, 2 mg/kg, once a day, on postnatal days 7-14. Then on postnatal day 60, the Morris water maze test was used to evaluate spatial learning and memory abilities. The open field test was carried out to assess anxiety-like activities. Phalloidin staining was performed to observe synaptic morphology in the hippocampus. Immunohistochemistry was used to count the number of NeuN-positive cells in the hippocampal CA1 region. DiI was applied to label dendritic spines. Calpeptin administration impaired spatial memory, caused anxiety-like behavior in adulthood, reduced the number and area of apical dendritic spines, and decreased actin polymerization in the hippocampus, but did not affect the number of NeuN-positive cells in the hippocampal CA1 region. For the neonatal experiments, neonatal rats were intraperitoneally injected with calpeptin, 2 mg/kg, on postnatal days 7 and 8. Western blot assay was performed to analyze the protein levels of Akt, Erk, p-Akt, p-Erk1/2, Erk1/2, SCOP, PTEN, mTOR, p-mTOR, CREB and p-CREB in the hippocampus. SCOP expression was increased, and the phosphorylation levels of Akt, mTOR and CREB were reduced in the hippocampus. These findings show that calpeptin administration after birth affects synaptic development in neonatal rats by inhibiting the Akt/mTOR signaling pathway, thereby perturbing hippocampal function. Therefore, calpeptin administration after birth is a risk factor for neurodevelopmental defects.
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Affiliation(s)
- Zhu-Jin Song
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - San-Juan Yang
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Lan Han
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Bin Wang
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Guoqi Zhu
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
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Yang J, Ju L, Yang C, Xue J, Setlow B, Morey TE, Gravenstein N, Seubert CN, Vasilopoulos T, Martynyuk AE. Effects of combined brief etomidate anesthesia and postnatal stress on amygdala expression of Cl - cotransporters and corticotropin-releasing hormone and alcohol intake in adult rats. Neurosci Lett 2018; 685:83-89. [PMID: 30125644 DOI: 10.1016/j.neulet.2018.08.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/09/2018] [Accepted: 08/16/2018] [Indexed: 01/18/2023]
Abstract
Early life stressors, including general anesthesia, can have adverse effects on adult neural and behavioral outcomes, such as disruptions in inhibitory signaling, stress responsivity and increased risk of psychiatric disorders. Here we used a rat model to determine the effects of combined exposure to etomidate (ET) neonatal anesthesia and maternal separation on adult amygdala expression of genes for corticotropin-releasing hormone (Crh) and the chloride co-transporters Nkcc1 and Kcc2, as well as ethanol intake. Male and female Sprague-Dawley rats were subjected to 2 h of ET anesthesia on postnatal days (P) 4, 5, or 6 followed by maternal separation for 3 h on P10 (ET + SEP). During the P91-P120 period rats had daily 2 h access to three 0.05% saccharin solutions containing 0%, 5%, or 10% ethanol, followed by gene expression analyses. The ET + SEP group had increased Crh mRNA levels and Nkcc1/Kcc2 mRNA ratios in the amygdala, with greater increases in Nkcc1/Kcc2 mRNA ratios in males. A moderate increase in 5% ethanol intake was evident in the ET + SEP males, but not females, after calculation of the ratio of alcohol intake between the last week and first week of exposure. In contrast, control males tended to decrease alcohol consumption during the same period. A brief exposure to ET combined with a subsequent episode of stress early in life induced significant alterations in expression of amygdala Crh, Nkcc1 and Kcc2 with greater changes in the Cl- transporter expression in males. The possibility of increased alcohol intake in the exposed males requires further confirmation using different alcohol intake paradigms.
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Affiliation(s)
- Jiaojiao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Lingsha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Chunyao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jinhu Xue
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Barry Setlow
- The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States; Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
| | - Christoph N Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Terrie Vasilopoulos
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States.
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Ju LS, Yang JJ, Morey TE, Gravenstein N, Seubert CN, Resnick JL, Zhang JQ, Martynyuk AE. Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats. Br J Anaesth 2018; 121:406-416. [PMID: 30032879 PMCID: PMC6200111 DOI: 10.1016/j.bja.2018.04.034] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 04/03/2018] [Accepted: 05/02/2018] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Clinical studies report learning disabilities and attention-deficit/hyperactivity disorders in those exposed to general anaesthesia early in life. Rats, primarily males, exposed to GABAergic anaesthetics as neonates exhibit behavioural abnormalities, exacerbated responses to stress, and reduced expression of hypothalamic K+-2Cl- Cl- exporter (Kcc2). The latter is implicated in development of psychiatric disorders, including male predominant autism spectrum disorders. We tested whether parental early life exposure to sevoflurane, the most frequently used anaesthetic in paediatrics, affects the next generation of unexposed rats. METHODS Offspring (F1) of unexposed or exposed to sevoflurane on postnatal day 5 Sprague-Dawley rats (F0) were subjected to behavioural and brain gene expression evaluations. RESULTS Male, but not female, progeny of sevoflurane-exposed parents exhibited abnormalities in behavioural testing and Kcc2 expression. Male F1 rats of both exposed parents exhibited impaired spatial memory and expression of hippocampal and hypothalamic Kcc2. Offspring of only exposed sires had abnormalities in elevated plus maze and prepulse inhibition of startle, but normal spatial memory and impaired expression of hypothalamic, but not hippocampal, Kcc2. In contrast to exposed F0, their progeny exhibited normal corticosterone responses to stress. Bisulphite sequencing revealed increased CpG site methylation in the Kcc2 promoter in F0 sperm and F1 male hippocampus and hypothalamus that was in concordance with the changes in Kcc2 expression in specific F1 groups. CONCLUSIONS Neonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.
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Affiliation(s)
- L-S Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - J-J Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - T E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - N Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA
| | - C N Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - J L Resnick
- Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - J-Q Zhang
- Department of Anesthesiology, Zhengzhou University, Zhengzhou, China
| | - A E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA.
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Grados M, Huselid R, Duque-Serrano L. Transcranial Magnetic Stimulation in Tourette Syndrome: A Historical Perspective, Its Current Use and the Influence of Comorbidities in Treatment Response. Brain Sci 2018; 8:brainsci8070129. [PMID: 29986411 PMCID: PMC6071080 DOI: 10.3390/brainsci8070129] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 06/25/2018] [Accepted: 06/28/2018] [Indexed: 11/25/2022] Open
Abstract
Background. Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder consisting of impairing motor and vocal tics which often persists adolescent and adult years. In this older refractory group, standard treatments such as pharmacotherapy and psychotherapeutic interventions may only have limited effects. Based on electrical cortical dysregulation in individuals with TS, a novel approach has employed brain stimulation strategies to modulate the putative aberrant neural electrical activity in pathways that may underlie tics, such as insula-supplementary motor area (SMA) connectivity. Methods. This review will examine all published clinical trials employing transcranial magnetic stimulation (TMS) to ameliorate tics, and discuss a framework for the pathophysiology of TS in relation to electrical brain activity. A framework for future research in tic disorders using TMS and imaging targeting neuroplasticity will be discussed. Results. Therapeutic electrical brain activity modulation with TMS has been carried out in stroke neuro-rehabilitation and neuropsychiatry, including trials in TS. Eleven trials document the use of TMS in TS targeting several brain areas, a positive effect is seen for those trials targeting the SMA. In particular, it appears that younger individuals with concurrent attention-deficit hyperactivity disorder (ADHD) benefit the most. Conclusions. TMS can be used as an effective tool to explore the psychophysiology of TS and potentially provide a therapeutic option. Ultimately, translational research using TMS in TS needs to explore connectivity differences pre- and post-treatment in individuals with TS that are linked to improvement in tic symptoms, with an emphasis on approaches using functional neuroimaging as well as other probes of neuroplasticity.
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Affiliation(s)
- Marco Grados
- Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
| | - Rachel Huselid
- Johns Hopkins University Krieger School of Arts & Sciences, Baltimore, MD 21205, USA.
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Neonatal maternal deprivation impairs localized de novo activity-induced protein translation at the synapse in the rat hippocampus. Biosci Rep 2018; 38:BSR20180118. [PMID: 29700212 PMCID: PMC5997792 DOI: 10.1042/bsr20180118] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/16/2018] [Accepted: 04/24/2018] [Indexed: 11/17/2022] Open
Abstract
Neonatal neuropsychiatric stress induces alterations in neurodevelopment that can lead to irreversible damage to neuronal physiology, and social, behavioral, and cognitive skills. In addition, this culminates to an elevated vulnerability to stress and anxiety later in life. Developmental deficits in hippocampal synaptic function and plasticity are among the primary contributors of detrimental alterations in brain function induced by early-life stress. However, the underlying molecular mechanisms are not completely understood. Localized protein translation, occurring at the synapse and triggered by neuronal activity, is critical for synapse function, maintenance, and plasticity. We used a rodent model of chronic maternal deprivation to characterize the effects of early-life neuropsychiatric stress on localized de novo protein translation at synaptic connections between neurons. Synaptoneurosomal preparations isolated biochemically from the hippocampi of rat pups that were subjected to maternal deprivation were deficient in depolarization-induced activity-dependent protein translation when compared with littermate controls. Conversely, basal unstimulated protein translation was not affected. Moreover, deficits in activity-driven synaptic protein translation were significantly correlated with a reduction in phosphorylated cell survival protein kinase protein B or Akt (p473 Ser and p308 Thr), but not phosphorylated extracellular signal-regulated kinase.
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Developmental excitatory-to-inhibitory GABA polarity switch is delayed in Ts65Dn mice, a genetic model of Down syndrome. Neurobiol Dis 2018; 115:1-8. [PMID: 29550538 DOI: 10.1016/j.nbd.2018.03.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 03/01/2018] [Accepted: 03/07/2018] [Indexed: 11/23/2022] Open
Abstract
Down syndrome (DS) is the most frequent genetic cause of developmental abnormalities leading to intellectual disability. One notable phenomenon affecting the formation of nascent neural circuits during late developmental periods is developmental switch of GABA action from depolarizing to hyperpolarizing mode. We examined properties of this switch in DS using primary cultures and acute hippocampal slices from Ts65Dn mice, a genetic model of DS. Cultures of DIV3-DIV13 Ts65Dn and control normosomic (2 N) neurons were loaded with FURA-2 AM, and GABA action was assessed using local applications. In 2 N cultures, the number of GABA-activated cells dropped from ~100% to 20% between postnatal days 3-13 (P3-P13) reflecting the switch in GABA action polarity. In Ts65Dn cultures, the timing of this switch was delayed by 2-3 days. Next, microelectrode recordings of multi-unit activity (MUA) were performed in CA3 slices during bath application of the GABAA agonist isoguvacine. MUA frequency was increased in P8-P12 and reduced in P14-P22 slices reflecting the switch of GABA action from excitatory to inhibitory mode. The timing of this switch was delayed in Ts65Dn by approximately 2 days. Finally, frequency of giant depolarizing potentials (GDPs), a form of primordial neural activity, was significantly increased in slices from Ts65Dn pups at P12 and P14. These experimental evidences show that GABA action polarity switch is delayed in Ts65Dn model of DS, and that these changes lead to a delay in maturation of nascent neural circuits. These alterations may affect properties of neural circuits in adult animals and, therefore, represent a prospective target for pharmacotherapy of cognitive impairment in DS.
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