|
1
|
Liu FW, Zhang XR, Cong YF, Liu YM, Zhang HT, Hou XQ. From postsynaptic neurons to astrocytes: the link between glutamate metabolism, Alzheimer's disease and Parkinson's disease. Rev Neurosci 2025:revneuro-2024-0143. [PMID: 40101161 DOI: 10.1515/revneuro-2024-0143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 02/28/2025] [Indexed: 03/20/2025]
Abstract
Glutamate is not only the main excitatory neurotransmitter of the human central nervous system, but also a potent neurotoxin. Therefore, maintaining low-dose, non-toxic extracellular glutamate concentrations between synapses to ensure the reliability of synaptic transmission is essential for maintaining normal physiological functions of neurons. More and more studies have confirmed that the specific pathogenesis of central nervous system diseases (such as Alzheimer's disease) caused by neuronal damage or death due to abnormal inter-synaptic glutamate concentration may be related to the abnormal function of excitatory amino acid transporter proteins and glutamine synthetase on astrocytes, and that the abnormal expression and function of the above two proteins may be related to the transcription, translation, and even modification of both by the process of transcription, translation, and even modification of astrocytes. oxidative stress, and inflammatory responses occurring in astrocytes during their transcription, translation and even modification. Therefore, in this review, we mainly discuss the relationship between glutamate metabolism (from postsynaptic neurons to astrocytes), Alzheimer's disease and Parkinson's disease in recent years.
Collapse
Affiliation(s)
- Fu-Wang Liu
- School of Pharmaceutical Sciences & Institute of Materia Medica, 518873 Shandong First Medical University & Shandong Academy of Medical Sciences , Jinan, Shandong, 250117, P.R. China
| | - Xue-Rui Zhang
- School of Pharmaceutical Sciences & Institute of Materia Medica, 518873 Shandong First Medical University & Shandong Academy of Medical Sciences , Jinan, Shandong, 250117, P.R. China
| | - Yi-Fan Cong
- Department of Pharmacy, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430014, P.R. China
| | - Yan-Man Liu
- School of Pharmaceutical Sciences & Institute of Materia Medica, 518873 Shandong First Medical University & Shandong Academy of Medical Sciences , Jinan, Shandong, 250117, P.R. China
| | - Han-Ting Zhang
- Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, Shandong, 266073, P.R. China
| | - Xue-Qin Hou
- School of Pharmaceutical Sciences & Institute of Materia Medica, 518873 Shandong First Medical University & Shandong Academy of Medical Sciences , Jinan, Shandong, 250117, P.R. China
| |
Collapse
|
|
2
|
Brain Morphological Characteristics of Cognitive Subgroups of Schizophrenia-Spectrum Disorders and Bipolar Disorder: A Systematic Review with Narrative Synthesis. Neuropsychol Rev 2023; 33:192-220. [PMID: 35194692 PMCID: PMC9998576 DOI: 10.1007/s11065-021-09533-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 11/23/2021] [Indexed: 10/19/2022]
Abstract
Despite a growing body of research, there is yet to be a cohesive synthesis of studies examining differences in brain morphology according to patterns of cognitive function among both schizophrenia-spectrum disorder (SSD) and bipolar disorder (BD) individuals. We aimed to provide a systematic overview of the morphological differences-inclusive of grey and white matter volume, cortical thickness, and cortical surface area-between cognitive subgroups of these disorders and healthy controls, and between cognitive subgroups themselves. An initial search of PubMed and Scopus databases resulted in 1486 articles of which 20 met inclusion criteria and were reviewed in detail. The findings of this review do not provide strong evidence that cognitive subgroups of SSD or BD map to unique patterns of brain morphology. There is preliminary evidence to suggest that reductions in cortical thickness may be more strongly associated with cognitive impairment, whilst volumetric deficits may be largely tied to the presence of disease.
Collapse
|
|
3
|
Alijanpour S, Miryounesi M, Ghafouri-Fard S. The role of excitatory amino acid transporter 2 (EAAT2) in epilepsy and other neurological disorders. Metab Brain Dis 2023; 38:1-16. [PMID: 36173507 DOI: 10.1007/s11011-022-01091-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/15/2022] [Indexed: 02/03/2023]
Abstract
Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). Excitatory amino acid transporters (EAATs) have important roles in the uptake of glutamate and termination of glutamatergic transmission. Up to now, five EAAT isoforms (EAAT1-5) have been identified in mammals. The main focus of this review is EAAT2. This protein has an important role in the pathoetiology of epilepsy. De novo dominant mutations, as well as inherited recessive mutation in this gene, have been associated with epilepsy. Moreover, dysregulation of this protein is implicated in a range of neurological diseases, namely amyotrophic lateral sclerosis, alzheimer's disease, parkinson's disease, schizophrenia, epilepsy, and autism. In this review, we summarize the role of EAAT2 in epilepsy and other neurological disorders, then provide an overview of the therapeutic modulation of this protein.
Collapse
Affiliation(s)
- Sahar Alijanpour
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Miryounesi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
4
|
Wang L, Ma T, Qiao D, Cui K, Bi X, Han C, Yang L, Sun M, Liu L. Polymorphism of rs12294045 in EAAT2 gene is potentially associated with schizophrenia in Chinese Han population. BMC Psychiatry 2022; 22:171. [PMID: 35260124 PMCID: PMC8903623 DOI: 10.1186/s12888-022-03799-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 02/11/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Recent studies have shown that the excitatory amino acid transporters (EAATs) are associated with schizophrenia. The aim of this study was to investigate the relationship between the polymorphism of EAAT1 and EAAT2 genes and schizophrenia in Chinese Han population. METHODS A total of 233 patients with schizophrenia and 342 healthy controls were enrolled. Two SNPs in EAAT1 gene (rs2269272, rs2731880) and four SNPs in EAAT2 gene (rs12360706, rs3088168, rs12294045, rs10836387) were genotyped by SNaPshot. Clinical features were collected using a self-made questionnaire. Psychotic symptoms of patients were measured by the Positive and Negative Syndrome Scale (PANSS), and patients' cognitive function was assessed by Matrics Consensus Cognitive Battery (MCCB). RESULTS Significant difference in allelic distributions between cases and controls was confirmed at locus rs12294045 (Ρ = 0.004) of EAAT2 gene. Different genotypes of rs12294045 were associated with family history (P = 0.046), in which patients with CT genotype had higher proportion of family history of psychosis. The polymorphism of rs12294045 was related to working operational memory (LNS: P = 0.016) and verbal learning function (HVLT-R: P = 0.042) in patients in which CT genotype had lower scores. However, these differences were no longer significant after Bonferroni correction. CONCLUSIONS Our study showed that the polymorphism of rs12294045 in EAAT2 gene may be associated with schizophrenia in Chinese Han population. CT genotype may be one of the risk factors for family history and cognitive deficits of patients.
Collapse
Affiliation(s)
- Lina Wang
- grid.27255.370000 0004 1761 1174Department of Psychiatry, Shandong Mental Health Center, Shandong University, No. 49 Wenhua Dong Road, Lixia District, Jinan, 250014 Shandong China
| | - Tantan Ma
- grid.27255.370000 0004 1761 1174Department of Psychiatry, Shandong Mental Health Center, Shandong University, No. 49 Wenhua Dong Road, Lixia District, Jinan, 250014 Shandong China
| | - Dongdong Qiao
- grid.27255.370000 0004 1761 1174Department of Psychiatry, Shandong Mental Health Center, Shandong University, No. 49 Wenhua Dong Road, Lixia District, Jinan, 250014 Shandong China
| | - Kaiyan Cui
- grid.27255.370000 0004 1761 1174Department of Psychiatry, Shandong Mental Health Center, Shandong University, No. 49 Wenhua Dong Road, Lixia District, Jinan, 250014 Shandong China
| | - Xiaojiao Bi
- grid.27255.370000 0004 1761 1174Department of Psychiatry, Shandong Mental Health Center, Shandong University, No. 49 Wenhua Dong Road, Lixia District, Jinan, 250014 Shandong China
| | - Chao Han
- grid.27255.370000 0004 1761 1174Department of Psychiatry, Shandong Mental Health Center, Shandong University, No. 49 Wenhua Dong Road, Lixia District, Jinan, 250014 Shandong China
| | - Limin Yang
- grid.27255.370000 0004 1761 1174Department of Psychiatry, Shandong Mental Health Center, Shandong University, No. 49 Wenhua Dong Road, Lixia District, Jinan, 250014 Shandong China
| | - Mengmeng Sun
- grid.27255.370000 0004 1761 1174Department of Psychiatry, Shandong Mental Health Center, Shandong University, No. 49 Wenhua Dong Road, Lixia District, Jinan, 250014 Shandong China
| | - Lanfen Liu
- Department of Psychiatry, Shandong Mental Health Center, Shandong University, No. 49 Wenhua Dong Road, Lixia District, Jinan, 250014, Shandong, China.
| |
Collapse
|
|
5
|
Brain morphology does not clearly map to cognition in individuals on the bipolar-schizophrenia-spectrum: a cross-diagnostic study of cognitive subgroups. J Affect Disord 2021; 281:776-785. [PMID: 33246649 DOI: 10.1016/j.jad.2020.11.064] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 11/08/2020] [Indexed: 01/11/2023]
Abstract
BACKGROUND Characterisation of brain morphological features common to cognitively similar individuals with bipolar disorder (BD) and schizophrenia spectrum disorders (SSD) may be key to understanding their shared neurobiological deficits. In the current study we examined whether three previously characterised cross-diagnostic cognitive subgroups differed among themselves and in comparison to healthy controls across measures of brain morphology. METHOD T1-weighted structural magnetic resonance imaging scans were obtained for 143 individuals; 65 healthy controls and 78 patients (SSD, n = 40; BD I, n = 38) classified into three cross-diagnostic cognitive subgroups: Globally Impaired (n = 24), Selectively Impaired (n = 32), and Superior/Near-Normal (n = 22). Cognitive subgroups were compared to each other and healthy controls on three separate analyses investigating (1) global, (2) regional, and (3) vertex-wise comparisons of brain volume, thickness, and surface area. RESULTS No significant subgroup differences were evident in global measures of brain morphology. In region of interest analyses, the Selectively Impaired subgroup had greater right accumbens volume than those Superior/Near-Normal subgroup and healthy controls, and the Superior/Near-Normal subgroup had reduced volume of the left entorhinal region compared to all other groups. In vertex-wise comparisons, the Globally Impaired subgroup had greater right precentral volume than the Selectively Impaired subgroup, and thicker cortex in the postcentral region relative to the Superior/Near-Normal subgroup. LIMITATIONS Exploration of medication effects was limited in our data. CONCLUSIONS Although some differences were evident in this sample, generally cross-diagnostic cognitive subgroups of individuals with SSD and BD did not appear to be clearly distinguished by patterns in brain morphology.
Collapse
|
|
6
|
Todd AC, Hardingham GE. The Regulation of Astrocytic Glutamate Transporters in Health and Neurodegenerative Diseases. Int J Mol Sci 2020; 21:E9607. [PMID: 33348528 PMCID: PMC7766851 DOI: 10.3390/ijms21249607] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 12/04/2020] [Accepted: 12/11/2020] [Indexed: 12/24/2022] Open
Abstract
The astrocytic glutamate transporters excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2) play a key role in nervous system function to maintain extracellular glutamate levels at low levels. In physiology, this is essential for the rapid uptake of synaptically released glutamate, maintaining the temporal fidelity of synaptic transmission. However, EAAT1/2 hypo-expression or hypo-function are implicated in several disorders, including epilepsy and neurodegenerative diseases, as well as being observed naturally with aging. This not only disrupts synaptic information transmission, but in extremis leads to extracellular glutamate accumulation and excitotoxicity. A key facet of EAAT1/2 expression in astrocytes is a requirement for signals from other brain cell types in order to maintain their expression. Recent evidence has shown a prominent role for contact-dependent neuron-to-astrocyte and/or endothelial cell-to-astrocyte Notch signalling for inducing and maintaining the expression of these astrocytic glutamate transporters. The relevance of this non-cell-autonomous dependence to age- and neurodegenerative disease-associated decline in astrocytic EAAT expression is discussed, plus the implications for disease progression and putative therapeutic strategies.
Collapse
Affiliation(s)
- Alison C. Todd
- UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School, Edinburgh EH16 4SB, UK;
- Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
| | - Giles E. Hardingham
- UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School, Edinburgh EH16 4SB, UK;
- Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
| |
Collapse
|
|
7
|
Barkus E. Effects of working memory training on emotion regulation: Transdiagnostic review. Psych J 2020; 9:258-279. [PMID: 32166891 DOI: 10.1002/pchj.353] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 10/20/2019] [Accepted: 11/19/2019] [Indexed: 12/18/2022]
Abstract
Working memory training is widely used transdiagnostically to improve cognition. However, more recently, studies using working memory training packages have targeted emotion-regulation outcomes to determine whether far transfer effects can be achieved. A narrative review is conducted of studies that have used standardized computerized working memory training packages across healthy volunteers, affect, anxiety, post-traumatic stress disorder (PTSD), and eating disordered populations with emotion-regulation outcomes. Working memory training has been used in children, adolescents, and adults to improve emotion regulation. Many studies have reported gains in mood as well as emotion-regulation strategies following working memory training, regardless of clinical indication and whether near transfer gains were achieved in cognitive domains. Significant emotion-regulation outcomes include: state and trait anxiety, rumination, brooding, positive appraisal, decreasing maladaptive emotion-regulation strategies, and decreasing intrusive thoughts. It is speculated that these far transfer outcomes from working memory training are possible due to the cognitive and neural overlap between cognitive and affective working memory, and emotion regulation. Working memory training could improve cognitive efficiency, which, in turn, increases the availability of cognitive resources during times when emotion regulation is taxed. Future studies need to consider the role of participant expectancy in predicting outcome measure performance, and including subjective and objective outcomes is paramount to study design. Furthermore, sample sizes require additional attention, given that the current review highlights that individual differences in non-clinical and clinical populations influence the outcomes from working memory training. Working memory training offers a possibility for improving emotion regulation transdiagnostically.
Collapse
Affiliation(s)
- Emma Barkus
- School of Psychology, University of Wollongong, Wollongong, Australia
| |
Collapse
|
|
8
|
Suárez-Pozos E, Thomason EJ, Fuss B. Glutamate Transporters: Expression and Function in Oligodendrocytes. Neurochem Res 2020; 45:551-560. [PMID: 30628017 PMCID: PMC6616022 DOI: 10.1007/s11064-018-02708-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/19/2018] [Accepted: 12/22/2018] [Indexed: 12/14/2022]
Abstract
Glutamate, the main excitatory neurotransmitter of the vertebrate central nervous system (CNS), is well known as a regulator of neuronal plasticity and neurodevelopment. Such glutamate function is thought to be mediated primarily by signaling through glutamate receptors. Thus, it requires a tight regulation of extracellular glutamate levels and a fine-tuned homeostasis that, when dysregulated, has been associated with a wide range of central pathologies including neuropsychiatric, neurodevelopmental, and neurodegenerative disorders. In the mammalian CNS, extracellular glutamate levels are controlled by a family of sodium-dependent glutamate transporters belonging to the solute carrier family 1 (SLC1) that are also referred to as excitatory amino acid transporters (EAATs). The presumed main function of EAATs has been best described in the context of synaptic transmission where EAATs expressed by astrocytes and neurons effectively regulate extracellular glutamate levels so that synapses can function independently. There is, however, increasing evidence that EAATs are expressed by cells other than astrocytes and neurons, and that they exhibit functions beyond glutamate clearance. In this review, we will focus on the expression and functions of EAATs in the myelinating cells of the CNS, oligodendrocytes. More specifically, we will discuss potential roles of oligodendrocyte-expressed EAATs in contributing to extracellular glutamate homeostasis, and in regulating oligodendrocyte maturation and CNS myelination by exerting signaling functions that have traditionally been associated with glutamate receptors. In addition, we will provide some examples for how dysregulation of oligodendrocyte-expressed EAATs may be involved in the pathophysiology of neurologic diseases.
Collapse
Affiliation(s)
- Edna Suárez-Pozos
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Box 980709, Richmond, VA, 23298, USA
| | - Elizabeth J Thomason
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Box 980709, Richmond, VA, 23298, USA
| | - Babette Fuss
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Box 980709, Richmond, VA, 23298, USA.
| |
Collapse
|
|
9
|
Pajarillo E, Rizor A, Lee J, Aschner M, Lee E. The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics. Neuropharmacology 2019; 161:107559. [PMID: 30851309 PMCID: PMC6731169 DOI: 10.1016/j.neuropharm.2019.03.002] [Citation(s) in RCA: 247] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 02/28/2019] [Accepted: 03/02/2019] [Indexed: 12/12/2022]
Abstract
Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS) which initiates rapid signal transmission in the synapse before its re-uptake into the surrounding glia, specifically astrocytes. The astrocytic glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) and their human homologs excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2), respectively, are the major transporters which take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with various neurological disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), manganism, ischemia, schizophrenia, epilepsy, and autism. While the mechanisms of neurological disorders are not well understood, the dysregulation of GLAST/GLT-1 may play a significant role in excitotoxicity and associated neuropathogenesis. The expression and function of GLAST/GLT-1 may be dysregulated at the genetic, epigenetic, transcriptional or translational levels, leading to high levels of extracellular glutamate and excitotoxicity. Consequently, understanding the regulatory mechanisms of GLAST/GLT-1 has been an area of interest in developing therapeutics for the treatment of neurological disorders. Pharmacological agents including β-lactam antibiotics, estrogen/selective estrogen receptor modulators (SERMs), growth factors, histone deacetylase inhibitors (HDACi), and translational activators have shown significant efficacy in enhancing the expression and function of GLAST/GLT-1 and glutamate uptake both in vitro and in vivo. This comprehensive review will discuss the regulatory mechanisms of GLAST/GLT-1, their association with neurological disorders, and the pharmacological agents which mediate their expression and function. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
Collapse
Affiliation(s)
- Edward Pajarillo
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL, 32301, USA
| | - Asha Rizor
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL, 32301, USA
| | - Jayden Lee
- Department of Speech, Language & Hearing Sciences, Boston University, Boston, MA, 02215, USA
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Eunsook Lee
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL, 32301, USA.
| |
Collapse
|
|
10
|
Penadés R, Bosia M, Catalán R, Spangaro M, García-Rizo C, Amoretti S, Bioque M, Bernardo M. The role of genetics in cognitive remediation in schizophrenia: A systematic review. SCHIZOPHRENIA RESEARCH-COGNITION 2019; 19:100146. [PMID: 31832337 PMCID: PMC6889757 DOI: 10.1016/j.scog.2019.100146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 04/08/2019] [Accepted: 04/17/2019] [Indexed: 12/12/2022]
Abstract
The role of genetics in cognitive remediation therapies in schizophrenia has not been completely understood yet. Different genes involved in neurotrophic, dopaminergic and serotonin systems have reported to influence cognitive functioning in schizophrenia. These genetic factors could also be contributing to the variability in responsiveness to cognitive treatments. No comprehensive synthesis of the literature of the role of genetics in the context of cognitive remediation has been conducted until now. We aimed to systematically review the published works through three electronic database searches: PubMed, Scopus, and the Cochrane Library. Eligible studies revealed a rising interest in the field although the number of published studies was rather small (n = 10). Eventually, promising results showing a relationship between some phenotypic variations based on different polymorphisms and different levels of responsivity to cognitive remediation therapies have been described although results are still inconclusive. In case those findings will be replicated, they could be guiding future research and informing clinical decision-making in the next future.
Collapse
Affiliation(s)
- Rafael Penadés
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Marta Bosia
- Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Rosa Catalán
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Marco Spangaro
- Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Clemente García-Rizo
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Silvia Amoretti
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Miquel Bioque
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| | - Miquel Bernardo
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic Barcelona, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
| |
Collapse
|
|
11
|
Thaweethee B, Suttajit S, Thanoi S, Dalton CF, Reynolds GP, Nudmamud-Thanoi S. Association of SLC1A2 and SLC17A7 polymorphisms with major depressive disorder in a Thai population. ASIAN BIOMED 2019. [DOI: 10.1515/abm-2019-0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Abstract
Background
Major depressive disorder (MDD) is a common psychiatric disorder with high prevalence and high risk of suicide. Genetic variation of glutamate transporters may associate with MDD and suicide attempt.
Objectives
To evaluate polymorphisms of excitatory amino acid transporter 2 gene (SLC1A2; rs752949, rs1885343, rs4755404, and rs4354668) and vesicular glutamate transporter 1 gene (SLC17A7; rs1043558, rs2946848, and rs11669017) in patients with MDD with and without suicide attempt, and determine the association of these polymorphisms with age of onset and severity of MDD.
Methods
DNA was extracted from blood taken from patients with MDD (n = 100; including nonsuicidal [n = 50] and suicidal [n = 50] subgroups) and controls (n = 100). Genotyping was conducted using TaqMan single-nucleotide polymorphism (SNP) genotyping.
Results
We found a significant difference in SLC17A7 rs2946848 genotype distribution between patients in the MDD and control groups (P = 0.016). Moreover, significant differences in SLC1A2 rs752949 (P = 0.022) and SLC17A7 rs2946848 (P = 0.026) genotype distributions were observed between patients in the nonsuicidal MDD and suicidal MDD groups. SLC1A2 rs1885343 A allele carriers showed significantly lower age of onset than GG genotype (P = 0.049). Furthermore, the severity of MDD indicated by the Hamilton Depression Rating Scale (HDRS) score of G allele carriers of SLC1A2 rs4755404 was significantly greater than the CC genotype (P = 0.013).
Conclusions
Polymorphisms of SLC1A2 and SLC17A7 may contribute to the risk of MDD and/or suicide attempt. An association of an SLC1A2 polymorphism with the severity of MDD was apparent.
Collapse
Affiliation(s)
- Benjamard Thaweethee
- Department of Anatomy, Faculty of Medical Science, Naresuan University , Phitsanulok 65000 , Thailand
- Centre of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University , Phitsanulok 65000 , Thailand
| | - Sirijit Suttajit
- Department of Psychiatry, Faculty of Medicine, Chiang Mai University , Chiang Mai 50200 , Thailand
| | - Samur Thanoi
- Department of Anatomy, Faculty of Medical Science, Naresuan University , Phitsanulok 65000 , Thailand
- Centre of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University , Phitsanulok 65000 , Thailand
| | - Caroline F. Dalton
- Biomolecular Sciences Research Centre, Sheffield Hallam University , Sheffield S1 1WB , UK
| | - Gavin P. Reynolds
- Centre of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University , Phitsanulok 65000 , Thailand
- Biomolecular Sciences Research Centre, Sheffield Hallam University , Sheffield S1 1WB , UK
| | - Sutisa Nudmamud-Thanoi
- Department of Anatomy, Faculty of Medical Science, Naresuan University , Phitsanulok 65000 , Thailand
- Centre of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University , Phitsanulok 65000 , Thailand
| |
Collapse
|
|
12
|
Mazza E, Spangaro M, Poletti S, Cavallaro R, Benedetti F. Genetic variability of glutamate reuptake: Effect on white matter integrity and working memory in schizophrenia. Schizophr Res 2019; 208:457-459. [PMID: 30857874 DOI: 10.1016/j.schres.2019.03.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/26/2019] [Accepted: 03/03/2019] [Indexed: 02/05/2023]
Affiliation(s)
- Elena Mazza
- Vita-Salute San Raffaele University, Milan, Italy
| | - Marco Spangaro
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
| | - Sara Poletti
- Vita-Salute San Raffaele University, Milan, Italy
| | - Roberto Cavallaro
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Francesco Benedetti
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| |
Collapse
|
|
13
|
Merk W, Kucia K, Mędrala T, Kowalczyk M, Owczarek A, Kowalski J. Association study of the excitatory amino acid transporter 2 (EAAT2) and glycine transporter 1 (GlyT1) gene polymorphism with schizophrenia in a Polish population. Neuropsychiatr Dis Treat 2019; 15:989-1000. [PMID: 31118638 PMCID: PMC6499478 DOI: 10.2147/ndt.s194924] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 02/14/2019] [Indexed: 01/28/2023] Open
Abstract
Background: Excitatory amino acid transporter 2 encoded by SLC1A2 is responsible for approximately 90% of glutamate uptake. Glycine transporter 1, encoded by SLC6A9, is responsible for maintaining a low concentration of the N-methyl-D-aspartate receptor (NMDAR) co-agonist - glycine in the synaptic cleft, suggesting its participation in the development of the NMDARs hypofunction described in schizophrenia. Aim: The aim of this study was to evaluate whether the functional polymorphism-181 A/C (rs4354668) of the SLC1A2 and the rs2486001 (IVS3+411 G/A) in the SLC6A9 are involved in schizophrenia development and its clinical picture in the Polish population. Methods: The study group consisted of 393 unrelated Caucasian patients (157 [39.9%] females and 236 [60.1%] males; mean age 41±12) diagnosed with schizophrenia according to the DSM-5, and 462 healthy controls. The results of the Positive and Negative Syndrome Scale (PANSS) were presented in the five-dimensional model. Polymorphisms of SLC1A2 and SLC6A9 were genotyped with the use of PCR-RFLP assay. Results: There were no statistically significant differences in the frequency of genotypes and alleles between the patients and controls for SLC1A2 and SLC6A9 polymorphisms in either the entire sample or after stratification according to gender. In the haplotype analysis, men with CA haplotype had more than 1.5 higher risk to develop schizophrenia than women (OR=1.63 [95% CI=1.17-2.27, p<0.05]). The influence of gender, genotypes of both analyzed polymorphisms and gender x genotype interactions on individual dimensions of the PANSS scale has not been observed. Also, there was no association of either polymorphism with suicide attempts. Conclusion: The results of the present study did not indicate an association of polymorphism-181 A/C (rs4354668) in SLC1A2 and rs2486001 in SLC6A9 with onset of schizophrenia and its psychopathology in a Polish population.
Collapse
Affiliation(s)
- Wojciech Merk
- Department of Psychiatry and Psychotherapy, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Krzysztof Kucia
- Department of Psychiatry and Psychotherapy, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Tomasz Mędrala
- Department of Psychiatry and Psychotherapy, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Małgorzata Kowalczyk
- Department of Medical Genetics, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Aleksander Owczarek
- Division of Statistics, Department of Instrumental Analysis, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland.,Department of Instrumental Analysis, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Jan Kowalski
- Department of Medical Genetics, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland
| |
Collapse
|
|
14
|
Spangaro M, Bosia M, Bechi M, Buonocore M, Cocchi F, Guglielmino C, Bianchi L, Mastromatteo A, Lorenzi C, Cavallaro R. Neurobiology of cognitive remediation in schizophrenia: Effects of EAAT2 polymorphism. Schizophr Res 2018; 202:106-110. [PMID: 30539765 DOI: 10.1016/j.schres.2018.06.059] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 03/27/2018] [Accepted: 06/24/2018] [Indexed: 12/20/2022]
Abstract
Cognitive deficits represent core features of schizophrenia, affecting quality of life and functioning. The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate reuptake and its activity is crucial for glutamatergic neurotransmission, prevention of excitotoxic damage and cerebral metabolism. Different studies reported that EAAT2 rs4354668 (-181 T/G) influences cognitive functions and brain structures in patients with schizophrenia. Specifically, the G allele, linked to lower EAAT2 expression, was associated with impaired prefrontal cognitive performance and reduced grey matter volumes. Cognitive remediation therapy (CRT) is one of the best available tool to treat cognitive deficits in schizophrenia, able to induce a neuroplastic modulation of cognitive functions. The present study aims to investigate the effects of rs4354668 on CRT outcome, also considering possible genotype interaction with antipsychotic (AP) treatment, since EAAT2 expression is negatively influenced by clozapine. We examined rs4354668 in 88 clinically stabilized patients with schizophrenia, treated with CRT and assessed at enrolment, at the end of CRT and after 3 months. We observed greater working memory improvements among patients carrying the T/T genotype, regardless of AP treatment. Moreover, we reported a significant interaction between pharmacological treatment and rs4354668 on executive functions, with greater improvements among T/T patients treated with APs other than clozapine. These observations suggest that impaired EAAT2 expression may attenuate CRT outcome. Moreover, our results indicate the possibility that rs4354668 could also differentially influence the response to CRT depending on the AP treatment.
Collapse
Affiliation(s)
- Marco Spangaro
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy.
| | - Marta Bosia
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Margherita Bechi
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy
| | - Mariachiara Buonocore
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy
| | - Federica Cocchi
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy
| | - Carmelo Guglielmino
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy
| | - Laura Bianchi
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy
| | - Antonella Mastromatteo
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy
| | - Cristina Lorenzi
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy
| | - Roberto Cavallaro
- IRCCS San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| |
Collapse
|
|
15
|
Parkin GM, Udawela M, Gibbons A, Dean B. Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders. World J Psychiatry 2018; 8:51-63. [PMID: 29988908 PMCID: PMC6033743 DOI: 10.5498/wjp.v8.i2.51] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 05/15/2018] [Accepted: 06/09/2018] [Indexed: 02/05/2023] Open
Abstract
Glutamate is the predominant excitatory neurotransmitter in the human brain and it has been shown that prolonged activation of the glutamatergic system leads to nerve damage and cell death. Following release from the pre-synaptic neuron and synaptic transmission, glutamate is either taken up into the pre-synaptic neuron or neighbouring glia by transmembrane glutamate transporters. Excitatory amino acid transporter (EAAT) 1 and EAAT2 are Na+-dependant glutamate transporters expressed predominantly in glia cells of the central nervous system. As the most abundant glutamate transporters, their primary role is to modulate levels of glutamatergic excitability and prevent spill over of glutamate beyond the synapse. This role is facilitated through the binding and transportation of glutamate into astrocytes and microglia. The function of EAAT1 and EAAT2 is heavily regulated at the levels of gene expression, post-transcriptional splicing, glycosylation states and cell-surface trafficking of the protein. Both glutamatergic dysfunction and glial dysfunction have been proposed to be involved in psychiatric disorder. This review will present an overview of the roles that EAAT1 and EAAT2 play in modulating glutamatergic activity in the human brain, and mount an argument that these two transporters could be involved in the aetiologies of schizophrenia and affective disorders as well as represent potential drug targets for novel therapies for those disorders.
Collapse
Affiliation(s)
- Georgia M Parkin
- Molecular Psychiatry Laboratory, the Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia
- CRC for Mental Health, Carlton VIC 3053, Australia
| | - Madhara Udawela
- Molecular Psychiatry Laboratory, the Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia
- CRC for Mental Health, Carlton VIC 3053, Australia
| | - Andrew Gibbons
- Molecular Psychiatry Laboratory, the Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia
| | - Brian Dean
- Molecular Psychiatry Laboratory, the Florey Institute of Neuroscience and Mental Health, Parkville VIC 3052, Australia
- CRC for Mental Health, Carlton VIC 3053, Australia
- Research Centre for Mental Health, the Faculty of Health, Arts and Design, Swinburne University, Hawthorne VIC 3122, Australia
| |
Collapse
|
|
16
|
Srikanth P, Lagomarsino VN, Muratore CR, Ryu SC, He A, Taylor WM, Zhou C, Arellano M, Young-Pearse TL. Shared effects of DISC1 disruption and elevated WNT signaling in human cerebral organoids. Transl Psychiatry 2018; 8:77. [PMID: 29643329 PMCID: PMC5895714 DOI: 10.1038/s41398-018-0122-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 12/12/2017] [Accepted: 01/31/2018] [Indexed: 12/26/2022] Open
Abstract
The development of three-dimensional culture methods has allowed for the study of developing cortical morphology in human cells. This provides a new tool to study the neurodevelopmental consequences of disease-associated mutations. Here, we study the effects of isogenic DISC1 mutation in cerebral organoids. DISC1 has been implicated in psychiatric disease based on genetic studies, including its interruption by a balanced translocation that increases the risk of major mental illness. Isogenic wild-type and DISC1-disrupted human-induced pluripotent stem cells were used to generate cerebral organoids, which were then examined for morphology and gene expression. We show that DISC1-mutant cerebral organoids display disorganized structural morphology and impaired proliferation, which is phenocopied by WNT agonism and rescued by WNT antagonism. Furthermore, there are many shared changes in gene expression with DISC1 disruption and WNT agonism, including in neural progenitor and cell fate markers, regulators of neuronal migration, and interneuron markers. These shared gene expression changes suggest mechanisms for the observed morphologic dysregulation with DISC1 disruption and points to new avenues for future studies. The shared changes in three-dimensional cerebral organoid morphology and gene expression with DISC1 interruption and WNT agonism further strengthens the link between DISC1 mutation, abnormalities in WNT signaling, and neuropsychiatric disease.
Collapse
Affiliation(s)
- Priya Srikanth
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Valentina N Lagomarsino
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Christina R Muratore
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Steven C Ryu
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Amy He
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Walter M Taylor
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Constance Zhou
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Marlise Arellano
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Tracy L Young-Pearse
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
17
|
Pollak TA, Drndarski S, Stone JM, David AS, McGuire P, Abbott NJ. The blood-brain barrier in psychosis. Lancet Psychiatry 2018; 5:79-92. [PMID: 28781208 DOI: 10.1016/s2215-0366(17)30293-6] [Citation(s) in RCA: 207] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 06/12/2017] [Accepted: 06/27/2017] [Indexed: 02/08/2023]
Abstract
Blood-brain barrier pathology is recognised as a central factor in the development of many neurological disorders, but much less is known about the role of the blood-brain barrier in psychiatric disorders. We review post-mortem, serum-biomarker, CSF-biomarker, and neuroimaging studies that have examined blood-brain barrier structure and function in schizophrenia and related psychoses. We consider how blood-brain barrier dysfunction could relate to glutamatergic and inflammatory abnormalities, which are increasingly understood to play a part in the pathogenesis of psychosis. Mechanisms by which the blood-brain barrier and its associated solute transporters moderate CNS availability of antipsychotic drugs are summarised. We conclude that the complex nature of blood-brain barrier dysfunction in psychosis might be relevant to many aspects of disrupted neuronal and synaptic function, increased permeability to inflammatory molecules, disrupted glutamate homoeostasis, impaired action of antipsychotics, and development of antipsychotic resistance. Future research should address the longitudinal course of blood-brain barrier alterations in psychosis, to determine whether blood-brain barrier dysfunction is a cause or consequence of the pathology associated with the disorder.
Collapse
Affiliation(s)
- Thomas A Pollak
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
| | | | - James M Stone
- Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Anthony S David
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Philip McGuire
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - N Joan Abbott
- Institute of Pharmaceutical Science, King's College London, London, UK
| |
Collapse
|
|
18
|
Thomas EH, Bozaoglu K, Rossell SL, Gurvich C. The influence of the glutamatergic system on cognition in schizophrenia: A systematic review. Neurosci Biobehav Rev 2017; 77:369-387. [DOI: 10.1016/j.neubiorev.2017.04.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 03/24/2017] [Accepted: 04/06/2017] [Indexed: 12/22/2022]
|
|
19
|
Murphy-Royal C, Dupuis J, Groc L, Oliet SHR. Astroglial glutamate transporters in the brain: Regulating neurotransmitter homeostasis and synaptic transmission. J Neurosci Res 2017; 95:2140-2151. [PMID: 28150867 DOI: 10.1002/jnr.24029] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 12/20/2016] [Accepted: 01/02/2017] [Indexed: 12/29/2022]
Abstract
Astrocytes, the major glial cell type in the central nervous system (CNS), are critical for brain function and have been implicated in various disorders of the central nervous system. These cells are involved in a wide range of cerebral processes including brain metabolism, control of central blood flow, ionic homeostasis, fine-tuning synaptic transmission, and neurotransmitter clearance. Such varied roles can be efficiently carried out due to the intimate interactions astrocytes maintain with neurons, the vasculature, as well as with other glial cells. Arguably, one of the most important functions of astrocytes in the brain is their control of neurotransmitter clearance. This is particularly true for glutamate whose timecourse in the synaptic cleft needs to be controlled tightly under physiological conditions to maintain point-to-point excitatory transmission, thereby limiting spillover and activation of more receptors. Most importantly, accumulation of glutamate in the extracellular space can trigger excessive activation of glutamatergic receptors and lead to excitotoxicity, a trademark of many neurodegenerative diseases. It is thus of utmost importance for both physiological and pathophysiological reasons to understand the processes that control glutamate time course within the synaptic cleft and regulate its concentrations in the extracellular space. © 2017 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Ciaran Murphy-Royal
- Neurocentre Magendie, Inserm U1215, Bordeaux, France.,Université de Bordeaux, Bordeaux, France
| | - Julien Dupuis
- Université de Bordeaux, Bordeaux, France.,Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, Bordeaux, France
| | - Laurent Groc
- Université de Bordeaux, Bordeaux, France.,Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, Bordeaux, France
| | - Stéphane H R Oliet
- Neurocentre Magendie, Inserm U1215, Bordeaux, France.,Université de Bordeaux, Bordeaux, France
| |
Collapse
|
|
20
|
Zhang B, Guan F, Chen G, Lin H, Zhang T, Feng J, Li L, Fu D. Common variants in SLC1A2 and schizophrenia: Association and cognitive function in patients with schizophrenia and healthy individuals. Schizophr Res 2015; 169:128-134. [PMID: 26459047 DOI: 10.1016/j.schres.2015.10.012] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 09/30/2015] [Accepted: 10/06/2015] [Indexed: 11/24/2022]
Abstract
SLC1A2 is reported to be responsible for the majority of glutamate uptake, which has a crucial role in neural development and synaptic plasticity, and a disturbance in glutamatergic transmission has been suggested to be involved in the pathophysiology of schizophrenia (SCZ) and cognition. To evaluate the relationship of common variants within SLC1A2 with SCZ and cognition in Han Chinese, 28 tag SNPs were genotyped in the discovery stage, which included 1117 cases and 2289 controls; significantly associated markers were genotyped in the replication stage with 2128 cases and 3865 controls. The rs4354668 SNP was identified to be significantly associated with SCZ in both datasets, and a similar pattern was also observed in the two-stage study on conducting imputation and haplotype association analyses. In addition, significant associations between the rs4354668 SNP and cognition were observed when processing the perseverative error of the Wisconsin Card Sorting Test in patients and controls. Our results provide supportive evidence for an effect of SLC1A2 on the etiology of SCZ, suggesting that genetic variation (rs4354668 and its haplotypes) in SLC1A2 may be involved in impaired executive function, which adds to the current body of knowledge regarding the risk of SCZ and the impairment of cognitive performance.
Collapse
Affiliation(s)
- Bao Zhang
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Fanglin Guan
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China; Institute of Human Genomics & Forensic Sciences, Xi'an, China.
| | - Gang Chen
- Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Huali Lin
- Xi'an Mental Health Center, Xi'an, Shannxi, China
| | - Tianxiao Zhang
- Department of Biology & Biomedical Sciences, Washington University in Saint Louis, MO, USA
| | - Jiali Feng
- School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Lu Li
- Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Dongke Fu
- Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Institute of Human Genomics & Forensic Sciences, Xi'an, China
| |
Collapse
|
|
21
|
Zeis T, Allaman I, Gentner M, Schroder K, Tschopp J, Magistretti PJ, Schaeren-Wiemers N. Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling. Brain Behav Immun 2015; 48:313-25. [PMID: 25937052 DOI: 10.1016/j.bbi.2015.04.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 04/10/2015] [Accepted: 04/11/2015] [Indexed: 01/22/2023] Open
Abstract
Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte-neuron lactate shuttle (ANLS) and the glutamate-glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1β signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1β and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1β in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients.
Collapse
Affiliation(s)
- T Zeis
- Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
| | - I Allaman
- Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - M Gentner
- Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
| | - K Schroder
- Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland; Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia
| | - J Tschopp
- Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland
| | - P J Magistretti
- Division of Biological and Environmental Sciences and Engineering, KAUST, Thuwal, Saudi Arabia; Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland; Centre de Neurosciences Psychiatriques, CHUV, Département de Psychiatrie, Site de Cery, CH-1008 Prilly/Lausanne, Switzerland
| | - N Schaeren-Wiemers
- Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
| |
Collapse
|
|
22
|
O'Donovan SM, Hasselfeld K, Bauer D, Simmons M, Roussos P, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE. Glutamate transporter splice variant expression in an enriched pyramidal cell population in schizophrenia. Transl Psychiatry 2015; 5:e579. [PMID: 26057049 PMCID: PMC4490284 DOI: 10.1038/tp.2015.74] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 02/02/2015] [Accepted: 03/01/2015] [Indexed: 12/27/2022] Open
Abstract
Dysregulation of the glutamate transporters EAAT1 and EAAT2 and their isoforms have been implicated in schizophrenia. EAAT1 and EAAT2 expression has been studied in different brain regions but the prevalence of astrocytic glutamate transporter expression masks the more subtle changes in excitatory amino acid transporters (EAATs) isoforms in neurons in the cortex. Using laser capture microdissection, pyramidal neurons were cut from the anterior cingulate cortex of postmortem schizophrenia (n = 20) and control (n = 20) subjects. The messenger RNA (mRNA) levels of EAAT1, EAAT2 and the splice variants EAAT1 exon9skipping, EAAT2 exon9skipping and EAAT2b were analyzed by real time PCR (RT-PCR) in an enriched population of neurons. Region-level expression of these transcripts was measured in postmortem schizophrenia (n = 25) and controls (n = 25). The relationship between selected EAAT polymorphisms and EAAT splice variant expression was also explored. Anterior cingulate cortex pyramidal cell expression of EAAT2b mRNA was increased (P < 0.001; 67%) in schizophrenia subjects compared with controls. There was no significant change in other EAAT variants. EAAT2 exon9skipping mRNA was increased (P < 0.05; 38%) at region level in the anterior cingulate cortex with no significant change in other EAAT variants at region level. EAAT2 single-nucleotide polymorphisms were significantly associated with changes in EAAT2 isoform expression. Haloperidol decanoate-treated animals, acting as controls for possible antipsychotic effects, did not have significantly altered neuronal EAAT2b mRNA levels. The novel finding that EAAT2b levels are increased in populations of anterior cingulate cortex pyramidal cells further demonstrates a role for neuronal glutamate transporter splice variant expression in schizophrenia.
Collapse
Affiliation(s)
- S M O'Donovan
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA
| | - K Hasselfeld
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA
| | - D Bauer
- Department of Neuroscience, Wellesley College, Wellesley, MA, USA
| | - M Simmons
- Department of Psychiatry, University of Alabama, Birmingham, AL, USA
| | - P Roussos
- Department of Psychiatry, Department of Genetics and Genomic Sciences, and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA,James J. Peters VA Medical Center, Mental Illness Research Education and Clinical Center, Bronx, NY, USA
| | - V Haroutunian
- Department of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - R E McCullumsmith
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA,Department of Neuroscience, Wellesley College, Wellesley, MA, USA,Department of Psychiatry, University of Alabama, Birmingham, AL, USA,Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, CARE 5830, 231 Albert Sabin Way Cincinnati, Cincinnati, OH 45267-0583, USA. E-mail:
| |
Collapse
|
|
23
|
Spangaro M, Bosia M, Zanoletti A, Bechi M, Mariachiara B, Pirovano A, Lorenzi C, Bramanti P, Smeraldi E, Cavallaro R. Exploring effects of EAAT polymorphisms on cognitive functions in schizophrenia. Pharmacogenomics 2015; 15:925-32. [PMID: 24956246 DOI: 10.2217/pgs.14.42] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
AIM To evaluate the effect of functional polymorphisms (rs4354668 and rs2731880) of the excitatory amino acid transporters (EAAT1 and 2) on the cognitive dysfunction that characterizes schizophrenia. MATERIALS & METHODS One hundred and ninety two subjects diagnosed with schizophrenia were assessed with Brief Assessment of Cognition in Schizophrenia, Wisconsin Card Sorting Test, Continuous Performance Test and N-back test and genotyped for rs4354668 and rs2731880. RESULTS ANOVA showed a significant difference among both EAAT1 and EAAT2 genotype groups on different cognitive measures. Worse performances were observed among carriers of the genotypes associated with lower EAAT expression. CONCLUSION RESULTS suggest that impaired activity and EAAT expression could influence cognitive performances in schizophrenia, thus representing a target of interest for development of pharmacological strategies aimed to improve cognition.
Collapse
Affiliation(s)
- Marco Spangaro
- San Raffaele Scientific Institute, Department of Clinical Neurosciences, Vita-Salute San Raffale University, Via Stamira d'Ancona 20, 20127 Milano, Italy
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Association of rare variation in the glutamate receptor gene SLC1A2 with susceptibility to bipolar disorder and schizophrenia. Eur J Hum Genet 2014; 23:1200-6. [PMID: 25406999 PMCID: PMC4351899 DOI: 10.1038/ejhg.2014.261] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 09/30/2014] [Accepted: 10/04/2014] [Indexed: 01/23/2023] Open
Abstract
The SLC1A2 gene encodes the excitatory amino acid transporter 2 (EAAT2). Glutamate is the major mediator of excitatory neurotransmission and EAAT2 is responsible for clearing the neurotransmitter from the synaptic cleft. Genetic variation in SLC1A2 has been implicated in a range of neurological and neuropsychiatric conditions including schizophrenia (SZ), autism and in core phenotypes of bipolar disorder (BD). The coding and putative regulatory regions of SLC1A2 gene were screened for variants using high resolution melting or sequenced in 1099 or in 32 BD subjects. Thirty-two variants were detected in the SLC1A2 gene. Fifteen potentially etiological variants were selected for genotyping in 1099 BD and 1095 control samples. Five amino acid changing variants were also genotyped in 630 participants suffering from SZ. None of the variants were found to be associated with BD or SZ or with the two diseases combined. However, two recurrent missense variants (rs145827578:G>A, p.(G6S); rs199599866:G>A, p.(R31Q)) and one recurrent 5′-untranslated region (UTR) variant (ss825678885:G>T) were detected in cases only. Combined analysis of the recurrent-case-only missense variants and of the case-only missense and 5′-UTR variants showed nominal evidence for association with the combined diseases (Fisher's P=0.019 and 0.0076). These findings are exploratory in nature and await replication in larger cohorts, however, they provide intriguing evidence that potentially functional rare variants in the SLC1A2 gene may confer susceptibility to psychotic disorders.
Collapse
|
|
25
|
Zhu X, Hao X, Luo J, Min S, Xie F, Zhang F. Propofol inhibits inflammatory cytokine-mediated glutamate uptake dysfunction to alleviate learning/memory impairment in depressed rats undergoing electroconvulsive shock. Brain Res 2014; 1595:101-9. [PMID: 25108038 DOI: 10.1016/j.brainres.2014.07.046] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Revised: 07/06/2014] [Accepted: 07/29/2014] [Indexed: 12/31/2022]
Abstract
Electroconvulsive therapy (ECT) is an effective treatment for major depression, but can result in memory impairment. Several studies have shown that anesthetic propofol can alleviate the impairment of memory induced by ECT. However, the underlying molecular mechanisms remain unclear. We aimed to investigate the effects of propofol and electroconvulsive shock (ECS, analog of ECT in animals) on hippocampal inflammatory cytokines and glutamate uptake in depressed rats. The chronic unpredictable mild stress (CUMS) procedure was adopted to establish a model of depression. Sixty adult Sprague-Dawley rats were randomly divided into 5 groups with the following assignments (n=12 for each group): group C: control group without treatment; group D: CUMS+sham ECS; group DE: CUMS+ECS; group DP: CUMS+propofol (80 mg/kg, i.p.); group DPE: CUMS+propofol (80 mg/kg, i.p.)+ECS. Sucrose preference test and Morris water maze were used to assess behavioral changes. Hippocampal glutamate levels were measured with high performance liquid chromatography and the expression levels of IL-1β, TNF-α, GLAST and GLT-1 was quantificational analyzed by real time PCR or Western Blotting. The results demonstrated that ECS increased the levels of IL-1β and TNF-α, down-regulated the expression of GLT-1, GLAST expression remains stable, heightened the concentration of glutamate in the hippocampus and aggravated learning and memory impairment of depressed rats. Propofol suppressed IL-1β and TNF-α production, up-regulated the expression of GLT-1, decreased the concentration of glutamate in the hippocampus and attenuated the impairment of learning and memory induced by ECS. Propofol alleviate the learning and memory impairment induced by ECS could be partly attributed to its anti-inflammatory effects. This article is part of a Special Issue entitled Brain and Memory.
Collapse
Affiliation(s)
- Xianlin Zhu
- Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
| | - Xuechao Hao
- Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Jie Luo
- Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Su Min
- Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
| | - Fei Xie
- Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Fan Zhang
- Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| |
Collapse
|
|
26
|
Genetic dys-regulation of astrocytic glutamate transporter EAAT2 and its implications in neurological disorders and manganese toxicity. Neurochem Res 2014; 40:380-8. [PMID: 25064045 DOI: 10.1007/s11064-014-1391-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 07/09/2014] [Accepted: 07/15/2014] [Indexed: 12/14/2022]
Abstract
Astrocytic glutamate transporters, the excitatory amino acid transporter (EAAT) 2 and EAAT1 (glutamate transporter 1 and glutamate aspartate transporter in rodents, respectively), are the main transporters for maintaining optimal glutamate levels in the synaptic clefts by taking up more than 90% of glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these transporters by various modes, such as single nucleotide polymorphisms and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via nuclear factor κB and cAMP response element binding protein at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics and translational regulation of EAAT2.
Collapse
|
|
27
|
Rial D, Lara DR, Cunha RA. The Adenosine Neuromodulation System in Schizophrenia. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2014; 119:395-449. [DOI: 10.1016/b978-0-12-801022-8.00016-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
|