|
1
|
Raj R, Dar SA, Wani ZA, Khare VK, Haq I. Association of neutrophil-to-lymphocyte ratio with antipsychotic administration in schizophrenia: A longitudinal study. Ind Psychiatry J 2025; 34:108-113. [PMID: 40376652 PMCID: PMC12077625 DOI: 10.4103/ipj.ipj_6_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 01/11/2025] [Accepted: 01/18/2025] [Indexed: 05/18/2025] Open
Abstract
Background Studies have hypothesized the role of the immune-inflammatory process behind the pathophysiology of psychiatric disorders like schizophrenia. Antipsychotic medication has been shown to suppress inflammatory response via complex mechanisms alleviating psychiatric symptoms. Aim To assess the relation of neutrophil-to-lymphocyte ratio (NLR) with antipsychotic administration and clinical symptomatology severity. Materials and Methods A longitudinal study was performed among 34 inpatients who fulfilled inclusion and exclusion criteria. Sociodemographic details were collected, and the brief psychiatric rating scale (BPRS) was applied during admission. Blood sampling was performed during baseline and at discharge for the NLR ratio (neutrophil count/lymphocyte count) with the application of BPRS. Results The mean ± SD age of the population was 38.91 ± 11.44 years, with male gender predominance (N = 25, 73.5%). The median duration of illness and duration of treatment were 10 months and 40 days, respectively. Twelve (35.3%) subjects were antipsychotic naïve. The mean ± SD of BPRS and NLR during admission was 49.94 ± 5.33 and 2.49 ± 0.92 and during discharge was 26.76 ± 6.04 and 2.08 ± 0.72, respectively. Conclusion The results confirmed the NLR-lowering effect of antipsychotics alongside lowering of clinical symptomatology. NLR has the potential to be a biomarker indicating antipsychotic treatment response.
Collapse
Affiliation(s)
- Rajnish Raj
- Department of Psychiatry, Institute of Mental Health and Neurosciences Kashmir, Government Medical College, Srinagar, Jammu and Kashmir, India
| | - Shabir Ahmad Dar
- Department of Psychiatry, Institute of Mental Health and Neurosciences Kashmir, Government Medical College, Srinagar, Jammu and Kashmir, India
| | - Zaid Ahmad Wani
- Department of Psychiatry, Institute of Mental Health and Neurosciences Kashmir, Government Medical College, Srinagar, Jammu and Kashmir, India
| | - Vaibhav Kumar Khare
- Department of Psychiatry, Institute of Mental Health and Neurosciences Kashmir, Government Medical College, Srinagar, Jammu and Kashmir, India
| | - Inaamul Haq
- Department of Community Medicine, Government Medical College, Srinagar, Jammu and Kashmir, India
| |
Collapse
|
|
2
|
Channer B, Matt SM, Nickoloff-Bybel EA, Pappa V, Agarwal Y, Wickman J, Gaskill PJ. Dopamine, Immunity, and Disease. Pharmacol Rev 2023; 75:62-158. [PMID: 36757901 PMCID: PMC9832385 DOI: 10.1124/pharmrev.122.000618] [Citation(s) in RCA: 104] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022] Open
Abstract
The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. Beyond these functions, a growing body of evidence indicates that dopamine is an important immunoregulatory factor. Most types of immune cells express dopamine receptors and other dopaminergic proteins, and many immune cells take up, produce, store, and/or release dopamine, suggesting that dopaminergic immunomodulation is important for immune function. Targeting these pathways could be a promising avenue for the treatment of inflammation and disease, but despite increasing research in this area, data on the specific effects of dopamine on many immune cells and disease processes remain inconsistent and poorly understood. Therefore, this review integrates the current knowledge of the role of dopamine in immune cell function and inflammatory signaling across systems. We also discuss the current understanding of dopaminergic regulation of immune signaling in the CNS and peripheral tissues, highlighting the role of dopaminergic immunomodulation in diseases such as Parkinson's disease, several neuropsychiatric conditions, neurologic human immunodeficiency virus, inflammatory bowel disease, rheumatoid arthritis, and others. Careful consideration is given to the influence of experimental design on results, and we note a number of areas in need of further research. Overall, this review integrates our knowledge of dopaminergic immunology at the cellular, tissue, and disease level and prompts the development of therapeutics and strategies targeted toward ameliorating disease through dopaminergic regulation of immunity. SIGNIFICANCE STATEMENT: Canonically, dopamine is recognized as a neurotransmitter involved in the regulation of movement, cognition, and reward. However, dopamine also acts as an immune modulator in the central nervous system and periphery. This review comprehensively assesses the current knowledge of dopaminergic immunomodulation and the role of dopamine in disease pathogenesis at the cellular and tissue level. This will provide broad access to this information across fields, identify areas in need of further investigation, and drive the development of dopaminergic therapeutic strategies.
Collapse
Affiliation(s)
- Breana Channer
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Stephanie M Matt
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Emily A Nickoloff-Bybel
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Vasiliki Pappa
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Yash Agarwal
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Jason Wickman
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Peter J Gaskill
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| |
Collapse
|
|
3
|
Nazari S, Pourmand SM, Makki SM, Brand S, Vousooghi N. Potential biomarkers of addiction identified by real-time PCR in human peripheral blood lymphocytes: a narrative review. Biomark Med 2022; 16:739-758. [PMID: 35658670 DOI: 10.2217/bmm-2021-0291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Addiction-related neurobiological factors could be considered as potential biomarkers. The concentration of peripheral biomarkers in tissues like blood lymphocytes may mirror their brain levels. This review is focused on the mRNA expression of potential addiction biomarkers in human peripheral blood lymphocytes (PBLs). PubMed, EMBASE, Web of Science, Scopus and Google Scholar were searched using the keywords 'addiction', 'biomarker', 'peripheral blood lymphocyte', 'gene expression' and 'real-time PCR'. The results showed the alterations in the regulation of genes such as dopamine receptors, opioid receptors, NMDA receptors, cannabinoid receptors, α-synuclein, DYN, MAO-A, FosB and orexin-A as PBLs biomarkers in addiction stages. Such variations could also be found during abstinence and relapse. PBLs biomarkers may help in drug development and have clinical implications.
Collapse
Affiliation(s)
- Shahrzad Nazari
- Department of Neuroscience & Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, 1417755469, Iran
| | - Seyed Mahmoud Pourmand
- Addiction Department, School of Behavioral Sciences & Mental Health (Tehran Institute of Psychiatry), Iran University of Medical Sciences, Tehran, 1445613111, Iran
| | - Seyed Mohammad Makki
- Department of Psychiatry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran
| | - Serge Brand
- Center for Affective-, Stress- and Sleep Disorders (ZASS), Psychiatric Clinics (UPK), University of Basel, Basel, 4002, Switzerland.,Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, 6714869914, Iran.,Substance Abuse Prevention Research Center, Kermanshah University of Medical Sciences, Kermanshah, 6714869914, Iran.,Department of Sport, Exercise, and Health, Division of Sport Science and Psychosocial Health, University of Basel, Basel, 4052, Switzerland.,Department of Psychiatry, School of Medicine, Tehran University of Medical Sciences, Tehran, 1417466191, Iran
| | - Nasim Vousooghi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, 1417755469, Iran.,Research Center for Cognitive & Behavioral Sciences, Tehran University of Medical Sciences, Tehran, 13337159140, Iran.,Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, 1336616357, Iran
| |
Collapse
|
|
4
|
Wagh VV, Vyas P, Agrawal S, Pachpor TA, Paralikar V, Khare SP. Peripheral Blood-Based Gene Expression Studies in Schizophrenia: A Systematic Review. Front Genet 2021; 12:736483. [PMID: 34721526 PMCID: PMC8548640 DOI: 10.3389/fgene.2021.736483] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/31/2021] [Indexed: 12/19/2022] Open
Abstract
Schizophrenia is a disorder that is characterized by delusions, hallucinations, disorganized speech or behavior, and socio-occupational impairment. The duration of observation and variability in symptoms can make the accurate diagnosis difficult. Identification of biomarkers for schizophrenia (SCZ) can help in early diagnosis, ascertaining the diagnosis, and development of effective treatment strategies. Here we review peripheral blood-based gene expression studies for identification of gene expression biomarkers for SCZ. A literature search was carried out in PubMed and Web of Science databases for blood-based gene expression studies in SCZ. A list of differentially expressed genes (DEGs) was compiled and analyzed for overlap with genetic markers, differences based on drug status of the participants, functional enrichment, and for effect of antipsychotics. This literature survey identified 61 gene expression studies. Seventeen out of these studies were based on expression microarrays. A comparative analysis of the DEGs (n = 227) from microarray studies revealed differences between drug-naive and drug-treated SCZ participants. We found that of the 227 DEGs, 11 genes (ACOT7, AGO2, DISC1, LDB1, RUNX3, SIGIRR, SLC18A1, NRG1, CHRNB2, PRKAB2, and ZNF74) also showed genetic and epigenetic changes associated with SCZ. Functional enrichment analysis of the DEGs revealed dysregulation of proline and 4-hydroxyproline metabolism. Also, arginine and proline metabolism was the most functionally enriched pathway for SCZ in our analysis. Follow-up studies identified effect of antipsychotic treatment on peripheral blood gene expression. Of the 27 genes compiled from the follow-up studies AKT1, DISC1, HP, and EIF2D had no effect on their expression status as a result of antipsychotic treatment. Despite the differences in the nature of the study, ethnicity of the population, and the gene expression analysis method used, we identified several coherent observations. An overlap, though limited, of genetic, epigenetic and gene expression changes supports interplay of genetic and environmental factors in SCZ. The studies validate the use of blood as a surrogate tissue for biomarker analysis. We conclude that well-designed cohort studies across diverse populations, use of high-throughput sequencing technology, and use of artificial intelligence (AI) based computational analysis will significantly improve our understanding and diagnostic capabilities for this complex disorder.
Collapse
Affiliation(s)
- Vipul Vilas Wagh
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Parin Vyas
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Suchita Agrawal
- The Psychiatry Unit, KEM Hospital and KEM Hospital Research Centre, Pune, India
| | | | - Vasudeo Paralikar
- The Psychiatry Unit, KEM Hospital and KEM Hospital Research Centre, Pune, India
| | - Satyajeet P Khare
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| |
Collapse
|
|
5
|
The role of dopamine receptors in lymphocytes and their changes in schizophrenia. Brain Behav Immun Health 2021; 12:100199. [PMID: 34589732 PMCID: PMC8474470 DOI: 10.1016/j.bbih.2021.100199] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 12/21/2020] [Indexed: 11/22/2022] Open
Abstract
Dopamine and its 5 receptors, which are grouped into two families (D1-like and D2-like), modulate functions at a systemic level in both the central nervous system and periphery. The central nervous system and the immune system are the main adaptive systems, which participate in a continuous and functional crosstalk to guarantee homeostasis. On binding to its 5 dopamine receptors, dopamine acts as a co-regulator of the immune system, contributing to the interaction of the central nervous system and inflammatory events and as a source of communication between the different immune cells. Dopaminergic perturbations in the central nervous system are observed in several neurological and psychiatric disorders. Schizophrenia is one of the most common mental disorders with a poorly understood pathoaetiology that includes genetic and environmental components that promote alterations in the dopaminergic system. Interestingly, abnormalities in dopamine receptors expression in lymphocytes of schizophrenia patients have been reported, often significantly correlating with the severity of the psychotic illness. Here, we review the current literature regarding the dopaminergic system in human lymphocytes and its alterations in schizophrenia.
The existence of DA in the bloodstream suggests the presence of dopaminergic components that modulate functions at a systemic level; therefore, its effects are not limited to the CNS and the signalling in the neuronal dopaminergic system should be independent from that of the peripheral systems. The effects by DA-mediated activation of different DRs on immune cells show different sensitivities to DA, but binding profiles of DA on T cells are similar to those in neuronal membranes, suggesting receptors act similarly to those found in neurons. All DRs are expressed on the LYM membrane. However, more detailed information is required on the expression patterns of DR in immune cells in healthy conditions and in pathologies. DA has been observed to influence LYM functions acting in a variety of important processes, like cytokine secretion, cell adhesion, chemotaxis, and cytotoxicity. In human LYM, DA on D1-like receptors decreases oxidative metabolism and apoptosis, activates the selective secretion of IL-10 and TNFα, and facilitates NK cells. In contrast, most of the immunostimulatory DA effects on LYM depend on stimulation of D2-like receptors including activation, proliferation, differentiation, and suppression of NK cells. To date, an altered expression or signalling of neurotransmitter receptors is observed in immune cells during psychiatric disorders and, consequently, these cells also markedly respond to antipsychotics. Numerous technologies have been used in search of biomarkers for SCZ. However, after a century of studying SCZ their application in psychiatry remains rare and there are currently no validated biomarkers for the diagnosis and prognosis of patients with SCZ or the prediction of treatment efficacy.
Collapse
|
|
6
|
Wysokiński A, Kozłowska E, Szczepocka E, Łucka A, Agier J, Brzezińska-Błaszczyk E, Sobierajska K. Expression of Dopamine D 1-4 and Serotonin 5-HT 1A-3A Receptors in Blood Mononuclear Cells in Schizophrenia. Front Psychiatry 2021; 12:645081. [PMID: 33776821 PMCID: PMC7988204 DOI: 10.3389/fpsyt.2021.645081] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/17/2021] [Indexed: 11/14/2022] Open
Abstract
Introduction: The aim of this study was to determine the mRNA expression profile of dopamine D1, D2, D3, D4 and serotonin 5-HT1A, 5-HT2A, and 5-HT3A receptors in peripheral blood mononuclear cells (PBMCs) in schizophrenia and the in vitro effect of antipsychotics on the expression of these receptors in PBMCs of healthy subjects. Materials and Methods: Twenty-seven patients with schizophrenia and 29 healthy controls were recruited for the study. All study subjects underwent thorough clinical assessment, including anthropometric and body composition measurements. The expression of mRNA for dopamine D1-4 and serotonin 5-HT1A-3A receptors was measured using quantitative RT-PCR in peripheral blood mononuclear cells. In vitro mRNA and protein expression of these receptors was measured using quantitative RT-PCR and Western Blotting in PBMCs cultured with quetiapine, haloperidol, aripiprazole, risperidone, olanzapine or clozapine at IC50, half of IC50, and one-quarter of IC50 concentrations. Results: The key finding was that the schizophrenia group demonstrated significantly higher mRNA expression of D1, D2 and D4 receptors (p < 0.001), and significantly lower mRNA expression of 5-HT3A receptors (p < 0.01). After adjusting for smoking, the mRNA expression of D1 lost its significance, while that of D3, 5-HT1A, 5-HT2A became significant (all three were lower in the schizophrenia group). These receptors also demonstrated different ratios of mRNA expression in the schizophrenia group. The in vitro experiments showed that high concentrations of antipsychotics influenced the mRNA and protein expression of all studied receptors. Conclusion: Schizophrenia patients display a distinctive pattern of dopamine and serotonin receptor mRNA expression in blood mononuclear cells. This expression is little affected by antipsychotic treatment and it may therefore serve as a useful diagnostic biomarker for schizophrenia.
Collapse
Affiliation(s)
- Adam Wysokiński
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
| | - Elżbieta Kozłowska
- Department of Experimental Immunology, Medical University of Lodz, Lodz, Poland
| | - Ewa Szczepocka
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
| | - Anna Łucka
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
| | - Justyna Agier
- Department of Experimental Immunology, Medical University of Lodz, Lodz, Poland
| | | | | |
Collapse
|
|
7
|
Zhou X, Wang X, Li R, Yan J, Xiao Y, Li W, Shen H. Neutrophil-to-Lymphocyte Ratio Is Independently Associated With Severe Psychopathology in Schizophrenia and Is Changed by Antipsychotic Administration: A Large-Scale Cross-Sectional Retrospective Study. Front Psychiatry 2020; 11:581061. [PMID: 33192726 PMCID: PMC7661461 DOI: 10.3389/fpsyt.2020.581061] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/18/2020] [Indexed: 12/21/2022] Open
Abstract
Background: Immunological and inflammatory mechanisms play an important role in schizophrenia. The neutrophil-to-lymphocyte ratio (NLR) is a value obtained by dividing the absolute number of neutrophils by the absolute lymphocyte count and represents a biomarker of systemic inflammatory response. There are studies investigating NLR association with psychopathology. However, the relationship has been only studied in small numbers of patients with schizophrenia, which leads to conflicting results and makes the meta-analytic data difficult to interpret. The aim of this study is to perform large-scale cross-sectional analysis on the potential correlation between NLR and disease severity in schizophrenic patients with or without medication. Methods: This cross-sectional retrospective study was conducted in Nanjing Medical University Affiliated Brain Hospital. We identified inpatients with schizophrenia between July 12, 2018 and March 27, 2019 and collected data of NLR, the Clinical Global Impression Severity scale (CGI-S) score and the Brief Psychiatric Rating Scale (BPRS) score. Results: The records of 1,144 identified patients (10.8% drug-free patients) were analyzed. We found that NLR was significantly decreased in schizophrenic patients after antipsychotic administration and there was the discrepant correlation between NLR and psychiatric symptoms in patients with or without antipsychotic medication. The results of multivariate logistic regressions showed that NLR was positively associated with the severity of disease (i.e., the CGI-S score and the BPRS total score) in drug-free patients, and it was negatively associated with the BPRS negative symptoms (i.e., the BPRS negative symptoms score) in drug-therapy patients. Conclusion: The study is the first to confirm the hypothesis that NLR is independently associated with severe psychopathology in schizophrenia and is changed by antipsychotic administration.
Collapse
Affiliation(s)
- Xia Zhou
- Neuro-Psychiatric Institute, Nanjing Medical University Affiliated Brain Hospital, Nanjing, China
| | - Xiaolan Wang
- Department of Psychiatry, Nanjing Medical University Affiliated Brain Hospital, Nanjing, China
| | - Rui Li
- School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Jun Yan
- Department of Geriatric Neurology, Nanjing Medical University Affiliated Brain Hospital, Nanjing, China
| | - Ying Xiao
- College of Science, China Pharmaceutical University, Nanjing, China
| | - Weiguang Li
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Hong Shen
- Neuro-Psychiatric Institute, Nanjing Medical University Affiliated Brain Hospital, Nanjing, China
| |
Collapse
|
|
8
|
Tavakkolifard M, Vousooghi N, Mahboubi S, Golab F, Ejtemaei Mehr S, Zarrindast MR. Evaluation of the relationship between the gene expression level of orexin-1 receptor in the rat blood and prefrontal cortex, novelty-seeking, and proneness to methamphetamine dependence: A candidate biomarker. Peptides 2020; 131:170368. [PMID: 32668268 DOI: 10.1016/j.peptides.2020.170368] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 06/19/2020] [Accepted: 07/06/2020] [Indexed: 01/01/2023]
Abstract
BACKGROUND previous studies have suggested that methamphetamine (METH) abuse may affect orexin regulation. However, the data regarding the relationship between the current level of orexin and the vulnerability to METH abuse are minimal. Here, we have investigated the correlation between the gene expression level of the orexin-1 receptor (OX1R) in the rat prefrontal cortex (PFC) and blood lymphocytes and susceptibility to METH dependence and its impact on novelty-seeking behavior. METHODS male Wistar rats were first examined for novelty-seeking behavior by the novel object recognition test, and the expression level of OX1R in their blood lymphocytes was evaluated by real-time PCR. Then, the susceptibility to METH abuse was investigated by voluntary METH oral consumption test. According to the amounts of METH consumption, the animals were divided into two groups of METH preferring and non-preferring. Half of the rats in each group were sacrificed, and the level of OX1R in their blood lymphocytes and PFC tissue was measured. The other half were sacrificed for the same reason after two weeks of drug abstinence. RESULTS The indexes of novelty-seeking behavior were significantly higher in the METH- preferring group compared to the non-preferring animals. Furthermore, the expression level of OX1R in the blood lymphocytes and PFC in the preferring group was considerably higher than the non-preferring group. CONCLUSION Up-regulation of the mRNA expression level of OX1R in the lymphocytes and PFC may predict vulnerability to the METH consumption and novelty-seeking, which may serve as a potential biomarker for METH abuse.
Collapse
Affiliation(s)
- Mahnoosh Tavakkolifard
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasim Vousooghi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran; Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran.
| | - Sara Mahboubi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fereshteh Golab
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shahram Ejtemaei Mehr
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zarrindast
- Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Cognitive Neuroscience, Institute for Cognitive Science Studies, Tehran, Iran.
| |
Collapse
|
|
9
|
Shahkarami K, Vousooghi N, Golab F, Mohsenzadeh A, Baharvand P, Sadat-Shirazi MS, Babhadi-Ashar N, Shakeri A, Zarrindast MR. Evaluation of dynorphin and kappa-opioid receptor level in the human blood lymphocytes and plasma: Possible role as a biomarker in severe opioid use disorder. Drug Alcohol Depend 2019; 205:107638. [PMID: 31710992 DOI: 10.1016/j.drugalcdep.2019.107638] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 08/31/2019] [Accepted: 09/16/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND The dynorphin (DYN)/kappa opioid receptor (KOR) system plays an important role in the development of addiction, and dysregulation of this system could lead to abnormal activity in the reward pathway. It has been reported that the expression state of the neurotransmitters and their receptors in the brain is reflected in peripheral blood lymphocytes (PBLs). METHODS We have evaluated the PBLs and plasma samples of four groups: 1) subjects with severe opioid use disorder (SOD), 2) methadone-maintenance treated (MMT) individuals, 3) long-term abstinent subjects having former SOD, and 4) healthy control subjects (n = 20 in each group). The mRNA expression level of preprodynorphin (pPDYN) and KOR in PBLs has been evaluated by real-time PCR. Peptide expression of PDYN in PBLs has been studied by western blot, and DYN concentration in plasma has been measured by ELISA. RESULTS The relative expression level of the pPDYN mRNA and PDYN peptide in PBLs were significantly up-regulated in SOD, MMT, and abstinent groups compared to control subjects. No significant difference was found in the plasma DYN concentration between study groups. The expression level of the KOR mRNA in PBLs was significantly decreased in all three study groups compared to the control subjects. CONCLUSION the expression changes in the DYN/KOR system after chronic exposure to opioids, including methadone, seems to be stable and does not return to normal levels even after 12 months abstinence. These long-time and permanent changes in PBLs may serve as a biomarker and footprint of SOD development in the periphery.
Collapse
Affiliation(s)
- Kourosh Shahkarami
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasim Vousooghi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran; Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran.
| | - Fereshteh Golab
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Azam Mohsenzadeh
- Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Parastoo Baharvand
- Department of Social Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Mitra-Sadat Sadat-Shirazi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Babhadi-Ashar
- Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Atena Shakeri
- Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zarrindast
- Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Cognitive Neuroscience, Institute for Cognitive Science Studies, Tehran, Iran.
| |
Collapse
|
|
10
|
Sadat-Shirazi MS, Vousooghi N, Alizadeh B, Makki SM, Zarei SZ, Nazari S, Zarrindast MR. Expression of NMDA receptor subunits in human blood lymphocytes: A peripheral biomarker in online computer game addiction. J Behav Addict 2018; 7:260-268. [PMID: 29788757 PMCID: PMC6174581 DOI: 10.1556/2006.7.2018.35] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background and aims Repeated performance of some behaviors such as playing computer games could result in addiction. The NMDA receptor is critically involved in the development of behavioral and drug addictions. It has been claimed that the expression level of neurotransmitter receptors in the brain may be reflected in peripheral blood lymphocytes (PBLs). Methods Here, using a real-time PCR method, we have investigated the mRNA expression of GluN2A, GluN2D, GluN3A, and GluN3B subunits of the NMDA receptor in PBLs of male online computer game addicts (n = 25) in comparison with normal subjects (n = 26). Results Expression levels of GluN2A, GluN2D, and GluN3B subunits were not statistically different between game addicts and the control group. However, the mRNA expression of the GluN3A subunit was downregulated in PBLs of game addicts. Discussion and conclusions Transcriptional levels of GluN2A and GluN2D subunits in online computer game addicts are similar to our previously reported data of opioid addiction and are not different from the control group. However, unlike our earlier finding of drug addiction, the mRNA expression levels of GluN3A and GluN3B subunits in PBLs of game addicts are reduced and unchanged, respectively, compared with control subjects. It seems that the downregulated state of the GluN3A subunit of NMDA receptor in online computer game addicts is a finding that deserves more studies in the future to see whether it can serve as a peripheral biomarker in addiction studies, where the researcher wants to rule out the confusing effects of abused drugs.
Collapse
Affiliation(s)
- Mitra-Sadat Sadat-Shirazi
- Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran,Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Nasim Vousooghi
- Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran,Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran,Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran,Corresponding author: Nasim Vousooghi, Pharm D, PhD; Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, PO Box 1417755469, Tehran, Iran; Phone: +98 21 8899 1118; Fax: +98 21 8899 1117; E-mail:
| | - Bentolhoda Alizadeh
- Department of Biology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Seyed Mohammad Makki
- Department of Psychiatry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Shahrzad Nazari
- Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zarrindast
- Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran,Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran,School of Cognitive Sciences, Institute for Studies in Theoretical Physics and Mathematics, Tehran, Iran,Institute for Cognitive Science Studies, Tehran, Iran
| |
Collapse
|
|
11
|
Liu L, Luo Y, Zhang G, Jin C, Zhou Z, Cheng Z, Yuan G. Correlation of DRD2 mRNA expression levels with deficit syndrome severity in chronic schizophrenia patients receiving clozapine treatment. Oncotarget 2017; 8:86515-86526. [PMID: 29156812 PMCID: PMC5689702 DOI: 10.18632/oncotarget.21230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 08/26/2017] [Indexed: 01/06/2023] Open
Abstract
Schizophrenia is a complex, severe, chronic psychiatric disorder, and the associated deficit syndrome is widely regarded as an important clinical aspect of schizophrenia. This study analyzed the relationship of deficit syndrome severity with the mRNA levels of members of signaling pathways that associate with the pathophysiology of schizophrenia, including the dopamine D2 receptor (DRD2), protein kinase B (AKT1), and phosphoinositide-3 kinase (PI3KCB), in peripheral blood leukocytes (PBLs) of 20 healthy controls and 19 chronic schizophrenia patients with long-term clozapine treatment. The DRD2 expression levels in chronic schizophrenia group were statistically higher than those in controls (t=2.168, p=0.037). Moreover, in chronic schizophrenia group, correlations were observed between the expression levels of DRD2 and PI3KCB (r=0.771, p<0.001), DRD2 and AKT1 (r=0.592, p=0.008), and PI3KCB and AKT1 (r=0.562, p=0.012) and between the DRD2 mRNA levels and the Proxy for the Deficit Syndrome score (r=0.511, p=0.025). In control group, the correlation between PI3KCB expression levels and DRD2 expression levels was only observed (r=0.782, p<0.001). In conclusion, a correlation was observed between increased deficit syndrome severity and elevated expression levels of DRD2 in PBLs of chronic schizophrenia patients receiving long-term clozapine treatment.
Collapse
Affiliation(s)
- Liang Liu
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
| | - Yin Luo
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
| | - Guofu Zhang
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
| | - Chunhui Jin
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
| | - Zhenhe Zhou
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
| | - Zaohuo Cheng
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
- Wuxi Tongren International Rehabilitation Hospital, Nanjing Medical University, Wuxi, China
| | - Guozhen Yuan
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
- Wuxi Tongren International Rehabilitation Hospital, Nanjing Medical University, Wuxi, China
| |
Collapse
|
|
12
|
Perkovic MN, Erjavec GN, Strac DS, Uzun S, Kozumplik O, Pivac N. Theranostic Biomarkers for Schizophrenia. Int J Mol Sci 2017; 18:E733. [PMID: 28358316 PMCID: PMC5412319 DOI: 10.3390/ijms18040733] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 03/23/2017] [Accepted: 03/27/2017] [Indexed: 12/14/2022] Open
Abstract
Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide.
Collapse
Affiliation(s)
| | | | - Dubravka Svob Strac
- Rudjer Boskovic Institute, Division of Molecular Medicine, 10000 Zagreb, Croatia.
| | - Suzana Uzun
- Clinic for Psychiatry Vrapce, 10090 Zagreb, Croatia.
| | | | - Nela Pivac
- Rudjer Boskovic Institute, Division of Molecular Medicine, 10000 Zagreb, Croatia.
| |
Collapse
|
|
13
|
Genis-Mendoza AD, Tovilla-Zárate CA, López-Narvaez L, Mendoza-Lorenzo P, Ostrosky-Wegman P, Nicolini H, González-Castro TB, Hernández-Diaz Y. Effect on the expression of drd2 and drd3 after neonatal lesion in the lymphocytes, nucleus accumbens, hippocampus and prefrontal cortex: comparative analysis between juvenile and adult Wistar rats. Hereditas 2016; 153:13. [PMID: 28096775 PMCID: PMC5226098 DOI: 10.1186/s41065-016-0018-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 10/27/2016] [Indexed: 01/10/2023] Open
Abstract
Background Neonatal lesion in the ventral hippocampus (NLVH) is a validated animal model to study schizophrenia from a neurodevelopmental perspective. This animal model is also used to investigate how neonatal lesions may alter the genetic expression of dopaminergic receptors. The present study compares mRNA expression levels of dopamine receptors (drd2 and drd3) in lymphocytes and brain of NLVH animals at two different age stages: young and adult. Methods The NLVH procedure was performed on 20 male Wistar rats at postnatal days 5–7. The mRNA expression levels of drd2 and drd3 genes in lymphocytes, nucleus accumbens, hippocampus and prefrontal cortex were measured and analyzed at postnatal days 45 and 90. The results were compared and contrasted with respective sham groups. Results In lymphocytes, only in NLVH-adult group we observed drd2 mRNA expression, while drd2 mRNA expression was not observed in the NLVH-juvenile rats; on the other hand, the drd3 mRNA expression did not show significant statistical differences. In hippocampus no differences were observed between drd2 mRNA or drd3 mRNA expression when comparing juvenile/adult shams with NLVH groups. In the prefrontal area, a decrease in drd2 mRNA expression levels were observed in the NLVH-adult group (F(1,3) = 52.83, p = 0,005) in comparison to the sham-adult group. Finally, in the nucleus accumbens, a strong decrease of drd3 mRNA expression was observed in the NLVH-adult group in comparison to the sham-adult group (F(1,3) = 123,2, p < 0.001). Conclusions Our results show that differences in drd2 and drd3 mRNA levels in NLVH-adults are patent when compared to the sham-adult group or with the NLVH-juvenile group. These findings suggest that the expression levels may be regulated during adulthood, leading to behavioral and neurochemical changes related to schizophrenia. Therefore, more studies are necessary to determine the role of dopamine receptors as possible molecular markers for neurodevelopmental changes associated with schizophrenia.
Collapse
Affiliation(s)
- Alma Delia Genis-Mendoza
- Instituto Nacional de Medicina Genómica (INMEGEN), Servicios de Atención Psiquiátrica (SAP), Secretaria de Salud, D.F. Mexico, Mexico
| | - Carlos Alfonso Tovilla-Zárate
- División Académica Multidisciplinaria de Comalcalco, Universidad Juárez Autónoma de Tabasco, Comalcalco, Tabasco Mexico
| | | | | | | | - Humberto Nicolini
- Instituto Nacional de Medicina Genómica (INMEGEN), Servicios de Atención Psiquiátrica (SAP), Secretaria de Salud, D.F. Mexico, Mexico ; Carracci Medical Group, Carracci 107. Insurgentes Extremadura, Ciudad de México, D.F. 13740 Mexico
| | - Thelma Beatriz González-Castro
- División Académica Multidisciplinaria de Jalpa de Méndez, Universidad Juárez Autónoma de Tabasco, Jalpa de Méndez, Tabasco Mexico
| | - Yazmin Hernández-Diaz
- División Académica Multidisciplinaria de Jalpa de Méndez, Universidad Juárez Autónoma de Tabasco, Jalpa de Méndez, Tabasco Mexico
| |
Collapse
|
|
14
|
Arreola R, Alvarez-Herrera S, Pérez-Sánchez G, Becerril-Villanueva E, Cruz-Fuentes C, Flores-Gutierrez EO, Garcés-Alvarez ME, de la Cruz-Aguilera DL, Medina-Rivero E, Hurtado-Alvarado G, Quintero-Fabián S, Pavón L. Immunomodulatory Effects Mediated by Dopamine. J Immunol Res 2016; 2016:3160486. [PMID: 27795960 PMCID: PMC5067323 DOI: 10.1155/2016/3160486] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 07/29/2016] [Accepted: 08/08/2016] [Indexed: 01/11/2023] Open
Abstract
Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R) and D2-like receptors (D2R, D3R, and D4R). The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS), there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers.
Collapse
Affiliation(s)
- Rodrigo Arreola
- Psychiatric Genetics Department, National Institute of Psychiatry “Ramón de la Fuente”, Clinical Research Branch, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Samantha Alvarez-Herrera
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Gilberto Pérez-Sánchez
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Enrique Becerril-Villanueva
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Carlos Cruz-Fuentes
- Psychiatric Genetics Department, National Institute of Psychiatry “Ramón de la Fuente”, Clinical Research Branch, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Enrique Octavio Flores-Gutierrez
- National Institute of Psychiatry “Ramón de la Fuente”, Clinical Research Branch, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - María Eugenia Garcés-Alvarez
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Dora Luz de la Cruz-Aguilera
- Laboratory of Neuroimmunoendocrinology, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Avenida Insurgentes Sur 3877, La Fama, Tlalpan, 14269 Mexico City, Mexico
| | - Emilio Medina-Rivero
- Unidad de Investigación y Desarrollo, Probiomed S.A. de C.V. Cruce de Carreteras Acatzingo-Zumpahuacán S/N, 52400 Tenancingo, MEX, Mexico
| | - Gabriela Hurtado-Alvarado
- Area of Neurosciences, Department of Biology of Reproduction, CBS, Universidad Autonoma Metropolitana, Unidad Iztapalapa, Avenida San Rafael Atlixco No. 186, Colonia Vicentina, Iztapalapa, 09340 Mexico City, Mexico
| | - Saray Quintero-Fabián
- Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Instituto Nacional de Pediatría, Av. del Iman No. 1, Cuarto Piso, 04530 Mexico City, Mexico
| | - Lenin Pavón
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| |
Collapse
|
|
15
|
Liu L, Luo Y, Zhang G, Jin C, Zhou Z, Cheng Z, Yuan G. The mRNA expression of DRD2, PI3KCB, and AKT1 in the blood of acute schizophrenia patients. Psychiatry Res 2016; 243:397-402. [PMID: 27449010 DOI: 10.1016/j.psychres.2016.07.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 06/03/2016] [Accepted: 07/04/2016] [Indexed: 10/21/2022]
Abstract
The phosphoinositide 3 kinase - protein kinase B (PI3K-Akt) signaling pathway plays an important role in the dopamine D2 receptor (DRD2) pathway and in the pathophysiology of schizophrenia. This study measured the mRNA levels of DRD2, PI3KCB, and AKT1 in peripheral blood samples from 24 acute schizophrenia patients and 20 healthy controls using real-time quantitative reverse transcription polymerase chain reaction (real-time qRT-PCR). We found that in the acute schizophrenia patients, the mRNA expression levels of DRD2 and PI3KCB were significantly lower than those in the healthy controls, while the AKT1 mRNA levels were significantly higher than those in the healthy controls. A significant relationship between the mRNA levels of DRD2 and PI3KCB was found only in the controls. In conclusion, the gene expression state of the DRD2-PI3K-AKT signaling cascade differed significantly between acute schizophrenia patients and healthy controls.
Collapse
Affiliation(s)
- Liang Liu
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China.
| | - Yin Luo
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
| | - Guofu Zhang
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
| | - Chunhui Jin
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
| | - Zhenhe Zhou
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
| | - Zaohuo Cheng
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China; Wuxi Tongren International Rehabilitation Hospital, Nanjing Medical University, Wuxi, China
| | - Guozhen Yuan
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China; Wuxi Tongren International Rehabilitation Hospital, Nanjing Medical University, Wuxi, China
| |
Collapse
|
|
16
|
Yoshino Y, Kawabe K, Mori T, Mori Y, Yamazaki K, Numata S, Nakata S, Yoshida T, Iga JI, Ohmori T, Ueno SI. Low methylation rates of dopamine receptor D2 gene promoter sites in Japanese schizophrenia subjects. World J Biol Psychiatry 2016; 17:449-56. [PMID: 27269479 DOI: 10.1080/15622975.2016.1197424] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVES According to the dopamine hypothesis, several studies on the gene for the dopamine receptor D2 (DRD2) have been conducted. However, no trait biomarkers on DRD2 are available. We examined whether the methylation rates in the upstream region of DRD2 in leukocytes are different in schizophrenia (SCZ) subjects compared to control subjects. METHODS We selected seven CpG sites in the upstream region of DRD2 that may theoretically bind major transcription factors. The methylation rates in these regions of 50 medicated and 18 drug-naïve SCZ subjects were compared with those of age-matched control subjects. RESULTS The methylation rates were significantly lower in medicated (CpG2, P < 0.0001; CpG4, P = 0.013; CpG7, P < 0.0001; and average: 12.9 ± 1.8 vs. 14.1 ± 2.2, P = 0.005) and drug-naïve SCZ subjects (CpG1, P = 0.006; CpG2, P = 0.001; CpG3, P = 0.001; CpG5, P = 0.02; CpG6, P = 0.015; CpG7, P = 0.027; and average: 9.86 ± 0.9 vs. 11.2 ± 1.3, P = 0.002). CONCLUSIONS We confirmed low methylation rates in the upstream region of DRD2 in both medicated and drug-naïve SCZ subjects. Low methylation rates of DRD2 in leukocytes may be a trait biomarker for SCZ.
Collapse
Affiliation(s)
- Yuta Yoshino
- a Department of Neuropsychiatry, Molecules and Function , Ehime University Graduate School of Medicine , Toon , Ehime , Japan
| | - Kentaro Kawabe
- a Department of Neuropsychiatry, Molecules and Function , Ehime University Graduate School of Medicine , Toon , Ehime , Japan
| | - Takaaki Mori
- a Department of Neuropsychiatry, Molecules and Function , Ehime University Graduate School of Medicine , Toon , Ehime , Japan
| | - Yoko Mori
- a Department of Neuropsychiatry, Molecules and Function , Ehime University Graduate School of Medicine , Toon , Ehime , Japan
| | - Kiyohiro Yamazaki
- a Department of Neuropsychiatry, Molecules and Function , Ehime University Graduate School of Medicine , Toon , Ehime , Japan
| | - Shusuke Numata
- b Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Biosciences , The University of Tokushima Graduate School , Tokushima , Japan
| | - Shunsuke Nakata
- a Department of Neuropsychiatry, Molecules and Function , Ehime University Graduate School of Medicine , Toon , Ehime , Japan
| | - Taku Yoshida
- a Department of Neuropsychiatry, Molecules and Function , Ehime University Graduate School of Medicine , Toon , Ehime , Japan
| | - Jun-Ichi Iga
- a Department of Neuropsychiatry, Molecules and Function , Ehime University Graduate School of Medicine , Toon , Ehime , Japan
| | - Tetsuro Ohmori
- b Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Biosciences , The University of Tokushima Graduate School , Tokushima , Japan
| | - Shu-Ichi Ueno
- a Department of Neuropsychiatry, Molecules and Function , Ehime University Graduate School of Medicine , Toon , Ehime , Japan
| |
Collapse
|
|
17
|
Abstract
The etiology and pathophysiology of schizophrenia and related mental disorders such as bipolar disorder and major depression remain largely unclear. Recent advances in mRNA profiling techniques made it possible to perform genome-wide gene expression analysis in a hypothesis-free manner. It was thought that this large-scale data mining approach would reveal unknown molecular cascades involved in mental disorders. Contrary to this initial expectation, however, DNA microarray results in psychiatric fields have been notoriously discordant. Here the authors review the findings of DNA microarray analysis, focusing on systematic gene expression changes in schizophrenia, as well as alterations in the expression of specific genes, that have been reported and replicated. The authors also address the probable causes for the discordance among studies, possible ways to solve the problem, and their preferred approach for data interpretation.
Collapse
Affiliation(s)
- Kazuya Iwamoto
- Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Saitama, Japan.
| | | |
Collapse
|
|
18
|
Lai CY, Scarr E, Udawela M, Everall I, Chen WJ, Dean B. Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics. World J Psychiatry 2016; 6:102-17. [PMID: 27014601 PMCID: PMC4804259 DOI: 10.5498/wjp.v6.i1.102] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/20/2015] [Accepted: 12/17/2015] [Indexed: 02/05/2023] Open
Abstract
Identifying biomarkers that can be used as diagnostics or predictors of treatment response (theranostics) in people with schizophrenia (Sz) will be an important step towards being able to provide personalized treatment. Findings from the studies in brain tissue have not yet been translated into biomarkers that are practical in clinical use because brain biopsies are not acceptable and neuroimaging techniques are expensive and the results are inconclusive. Thus, in recent years, there has been search for blood-based biomarkers for Sz as a valid alternative. Although there are some encouraging preliminary data to support the notion of peripheral biomarkers for Sz, it must be acknowledged that Sz is a complex and heterogeneous disorder which needs to be further dissected into subtype using biological based and clinical markers. The scope of this review is to critically examine published blood-based biomarker of Sz, focusing on possible uses for diagnosis, treatment response, or their relationship with schizophrenia-associated phenotype. We sorted the studies into six categories which include: (1) brain-derived neurotrophic factor; (2) inflammation and immune function; (3) neurochemistry; (4) oxidative stress response and metabolism; (5) epigenetics and microRNA; and (6) transcriptome and proteome studies. This review also summarized the molecules which have been conclusively reported as potential blood-based biomarkers for Sz in different blood cell types. Finally, we further discusses the pitfall of current blood-based studies and suggest that a prediction model-based, Sz specific, blood oriented study design as well as standardize blood collection conditions would be useful for Sz biomarker development.
Collapse
|
|
19
|
Wu JQ, Green MJ, Gardiner EJ, Tooney PA, Scott RJ, Carr VJ, Cairns MJ. Altered neural signaling and immune pathways in peripheral blood mononuclear cells of schizophrenia patients with cognitive impairment: A transcriptome analysis. Brain Behav Immun 2016; 53:194-206. [PMID: 26697997 DOI: 10.1016/j.bbi.2015.12.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 11/26/2015] [Accepted: 12/13/2015] [Indexed: 12/20/2022] Open
Abstract
Cognitive deficits are a core feature of schizophrenia and contribute significantly to functional disability. We investigated the molecular pathways associated with schizophrenia (SZ; n=47) cases representing both 'cognitive deficit' (CD; n=22) and 'cognitively spared' (CS; n=25) subtypes of schizophrenia (based on latent class analysis of 9 cognitive performance indicators), compared with 49 healthy controls displaying 'normal' cognition. This was accomplished using gene-set analysis of transcriptome data derived from peripheral blood mononuclear cells (PBMCs). We detected 27 significantly altered pathways (19 pathways up-regulated and 8 down-regulated) in the combined SZ group and a further 6 pathways up-regulated in the CS group and 5 altered pathways (4 down-regulated and 1 up-regulated) in the CD group. The transcriptome profiling in SZ and cognitive subtypes were characterized by the up-regulated pathways involved in immune dysfunction (e.g., antigen presentation in SZ), energy metabolism (e.g., oxidative phosphorylation), and down-regulation of the pathways involved in neuronal signaling (e.g., WNT in SZ/CD and ERBB in SZ). When we looked for pathways that differentiated the two cognitive subtypes we found that the WNT signaling was significantly down-regulated (FDR<0.05) in the CD group in accordance with the combined SZ cohort, whereas it was unaffected in the CS group. This suggested suppression of WNT signaling was a defining feature of cognitive decline in schizophrenia. The WNT pathway plays a role in both the development/function of the central nervous system and peripheral tissues, therefore its alteration in PBMCs may be indicative of an important genomic axis relevant to cognition in the neuropathology of schizophrenia.
Collapse
Affiliation(s)
- Jing Qin Wu
- School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Schizophrenia Research Institute, Sydney, Australia; Centre for Translational Neuroscience and Mental Health, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia
| | - Melissa J Green
- Schizophrenia Research Institute, Sydney, Australia; School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
| | - Erin J Gardiner
- School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Schizophrenia Research Institute, Sydney, Australia; Centre for Translational Neuroscience and Mental Health, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia
| | - Paul A Tooney
- School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Schizophrenia Research Institute, Sydney, Australia
| | - Rodney J Scott
- School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Schizophrenia Research Institute, Sydney, Australia; Centre for Translational Neuroscience and Mental Health, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia
| | - Vaughan J Carr
- Schizophrenia Research Institute, Sydney, Australia; School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
| | - Murray J Cairns
- School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia; Schizophrenia Research Institute, Sydney, Australia; Centre for Translational Neuroscience and Mental Health, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia.
| |
Collapse
|
|
20
|
Cui Y, Prabhu V, Nguyen TB, Yadav BK, Chung YC. The mRNA Expression Status of Dopamine Receptor D2, Dopamine Receptor D3 and DARPP-32 in T Lymphocytes of Patients with Early Psychosis. Int J Mol Sci 2015; 16:26677-86. [PMID: 26561806 PMCID: PMC4661842 DOI: 10.3390/ijms161125983] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 10/22/2015] [Accepted: 10/23/2015] [Indexed: 01/22/2023] Open
Abstract
Peripheral blood lymphocytes are an attractive tool because there is accumulating evidence indicating that lymphocytes may be utilized as a biomarker in the field of psychiatric study as they could reveal the condition of cells distributed in the brain. Here, we measured the mRNA expression status of dopamine receptor D2 (DRD2), DRD3, and dopamine and cyclic adenosine 3',5'-monophosphate regulated phosphoprotein-32 (DARPP-32) in T lymphocytes of patients with early psychosis by quantitative real-time polymerase chain reaction (q-PCR) and explored the relationships between their mRNA levels and the psychopathological status of patients. The present study demonstrated that the mRNA expression levels of DRD3 in T lymphocytes were significantly different among controls, and in patients with psychotic disorder not otherwise specified (NOS) and schizophrenia/schizophreniform disorder. However, no significant differences in mRNA expression levels of DRD2 and DARPP-32 were found among the three groups. We found a significant positive correlation between the DRD2 mRNA level and the score of the excited factor of the Positive and Negative Syndrome Scale (PANSS) in patients with schizophrenia/schizophreniform disorder. These findings suggest that DRD3 mRNA levels may serve as a potential diagnostic biomarker differentiating patients with early psychosis from controls.
Collapse
Affiliation(s)
- Yin Cui
- Department of Psychiatry, Chonbuk National University Medical School, Jeonju 561-756, Korea.
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 561-756, Korea.
| | - Vishwanath Prabhu
- Department of Psychiatry, Chonbuk National University Medical School, Jeonju 561-756, Korea.
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 561-756, Korea.
| | - Thong Ba Nguyen
- Department of Psychiatry, Chonbuk National University Medical School, Jeonju 561-756, Korea.
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 561-756, Korea.
| | - Binod Kumar Yadav
- Department of Psychiatry, Chonbuk National University Medical School, Jeonju 561-756, Korea.
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 561-756, Korea.
| | - Young-Chul Chung
- Department of Psychiatry, Chonbuk National University Medical School, Jeonju 561-756, Korea.
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 561-756, Korea.
| |
Collapse
|
|
21
|
Storozheva ZI, Kirenskaya AV, Proshin AT. The neuromediator mechanisms of the cognitive deficit in schizophrenia. NEUROCHEM J+ 2015. [DOI: 10.1134/s1819712415030095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
|
|
22
|
Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment. J Neuroimmune Pharmacol 2015; 10:610-9. [PMID: 26162591 DOI: 10.1007/s11481-015-9626-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 07/03/2015] [Indexed: 12/21/2022]
Abstract
Schizophrenia is a severe and highly complex neurodevelopmental disorder with an unknown etiopathology. Recently, immunopathogenesis has emerged as one of the most compelling etiological models of schizophrenia. Over the past few years considerable research has been devoted to the role of innate immune responses in schizophrenia. The findings of such studies have helped to conceptualize schizophrenia as a chronic low-grade inflammatory disorder. Although the contribution of adaptive immune responses has also been emphasized, however, the precise role of T cells in the underlying neurobiological pathways of schizophrenia is yet to be ascertained comprehensively. T cells have the ability to infiltrate brain and mediate neuro-immune cross-talk. Conversely, the central nervous system and the neurotransmitters are capable of regulating the immune system. Neurotransmitter like dopamine, implicated widely in schizophrenia risk and progression can modulate the proliferation, trafficking and functions of T cells. Within brain, T cells activate microglia, induce production of pro-inflammatory cytokines as well as reactive oxygen species and subsequently lead to neuroinflammation. Importantly, such processes contribute to neuronal injury/death and are gradually being implicated as mediators of neuroprogressive changes in schizophrenia. Antipsychotic drugs, commonly used to treat schizophrenia are also known to affect adaptive immune system; interfere with the differentiation and functions of T cells. This understanding suggests a pivotal role of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review.
Collapse
|
|
23
|
Vousooghi N, Zarei SZ, Sadat-Shirazi MS, Eghbali F, Zarrindast MR. mRNA expression of dopamine receptors in peripheral blood lymphocytes of computer game addicts. J Neural Transm (Vienna) 2015; 122:1391-8. [DOI: 10.1007/s00702-015-1408-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 05/04/2015] [Indexed: 12/24/2022]
|
|
24
|
Xu Y, Chen XT, Luo M, Tang Y, Zhang G, Wu D, Yang B, Ruan DY, Wang HL. Multiple epigenetic factors predict the attention deficit/hyperactivity disorder among the Chinese Han children. J Psychiatr Res 2015; 64:40-50. [PMID: 25840828 DOI: 10.1016/j.jpsychires.2015.03.006] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 03/06/2015] [Accepted: 03/11/2015] [Indexed: 11/30/2022]
Abstract
Attention deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. Despite its prevalence, the critical factors involved in its development remain to be identified. It was recently suggested that epigenetic mechanisms probably contribute to the etiology of ADHD. The present study was designed to examine the associations of epigenetic markers with ADHD among Chinese Han children, aiming to establish the prediction model for this syndrome from the epigenetic perspective. We conducted a pair-matching case-control study, and the ADHD children were systematically evaluated via structured diagnostic interviews, including caregiver interviews, based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, revised criteria (DSM-IV-R). The expression levels of risk genes DAT1, DRD4, DRD5, as well as their promoter methylation, were determined respectively, followed by the expression profiles of histone-modifying genes p300, MYST4, HDAC1, MeCP2. The multivariate logistic regressions were performed to establish ADHD prediction models. All of the seven genes tested were identified as risk factors for ADHD. The methylation of one critical CpG site located upstream of DRD4 was shown to affect its transcription, suggesting a role in ADHD's development. Aberrant DNA methylation and histone acetylation were indicated in ADHD patients. In addition, a prediction model was established using the combination of p300, MYST4 and HDAC1, with the accuracy of 0.9338. This is, to our knowledge, the first study to clearly demonstrate the associations between epigenetic markers and ADHD, shedding light on the preliminary diagnosis and etiological studies of this widespread disorder.
Collapse
Affiliation(s)
- Yi Xu
- School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, Anhui Province, 230009, PR China.
| | - Xiang-Tao Chen
- School of Pharmacy, Anhui Medical University, Hefei, Anhui Province, 230031, PR China.
| | - Man Luo
- School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, Anhui Province, 230009, PR China.
| | - Yuqing Tang
- School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, Anhui Province, 230009, PR China.
| | - Guangxiang Zhang
- Biostatistics and Data Management Core, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA.
| | - De Wu
- Department of Pediatrics, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230022, PR China.
| | - Bin Yang
- Department of Child Neurology, Anhui Provincial Children's Hospital, Hefei, Anhui Province, 230031, PR China.
| | - Di-Yun Ruan
- School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, Anhui Province, 230009, PR China; School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
| | - Hui-Li Wang
- School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, Anhui Province, 230009, PR China.
| |
Collapse
|
|
25
|
Csonka C, Kupai K, Bencsik P, Görbe A, Pálóczi J, Zvara A, Puskás LG, Csont T, Ferdinandy P. Cholesterol-enriched diet inhibits cardioprotection by ATP-sensitive K+ channel activators cromakalim and diazoxide. Am J Physiol Heart Circ Physiol 2013; 306:H405-13. [PMID: 24285110 DOI: 10.1152/ajpheart.00257.2013] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It has been previously shown that hyperlipidemia interferes with cardioprotective mechanisms. Here, we investigated the interaction of hyperlipidemia with cardioprotection induced by pharmacological activators of ATP-sensitive K(+) (KATP) channels. Hearts isolated from rats fed a 2% cholesterol-enriched diet or normal diet for 8 wk were subjected to 30 min of global ischemia and 120 min of reperfusion in the presence or absence of KATP modulators. In normal diet-fed rats, either the nonselective KATP activator cromakalim at 10(-5) M or the selective mitochondrial (mito)KATP opener diazoxide at 3 × 10(-5) M significantly decreased infarct size compared with vehicle-treated control rats. Their cardioprotective effect was abolished by coadministration of the nonselective KATP blocker glibenclamide or the selective mitoKATP blocker 5-hydroxydecanoate, respectively. However, in cholesterol-fed rats, the cardioprotective effect of cromakalim or diazoxide was not observed. Therefore, we further investigated how cholesterol-enriched diet influences cardiac KATP channels. Cardiac expression of a KATP subunit gene (Kir6.1) was significantly downregulated in cholesterol-fed rats; however, protein levels of Kir6.1 and Kir6.2 were not changed. The cholesterol diet significantly decreased cardiac ATP, increased lactate content, and enhanced myocardial oxidative stress, as shown by increased cardiac superoxide and dityrosine formation. This is the first demonstration that cardioprotection by KATP channel activators is impaired in cholesterol-enriched diet-induced hyperlipidemia. The background mechanism may include hyperlipidemia-induced attenuation of mitoKATP function by altered energy metabolism and increased oxidative stress in the heart.
Collapse
Affiliation(s)
- Csaba Csonka
- Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary
| | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Liu L, Yuan G, Cheng Z, Zhang G, Liu X, Zhang H. Identification of the mRNA expression status of the dopamine D2 receptor and dopamine transporter in peripheral blood lymphocytes of schizophrenia patients. PLoS One 2013; 8:e75259. [PMID: 24086483 PMCID: PMC3783374 DOI: 10.1371/journal.pone.0075259] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 08/13/2013] [Indexed: 01/13/2023] Open
Abstract
The aim of this study was to detect the mRNA expression levels of the dopamine D2 receptor (DRD2) and dopamine transporter (DAT) in peripheral blood leukocytes (PBLs) of schizophrenia patients and to explore the relationship between the mRNA expression levels and the clinical symptoms of schizophrenia. The research included 25 cases of acute schizophrenia patients, 27 cases of chronic schizophrenia patients, and 30 healthy controls. In every case, we measured the mRNA levels of DRD2 and DAT in PBLs by real-time quantitative reverse transcription-polymerase chain reaction (real-time RT-PCR), and we evaluated the patients' clinical symptoms using the Positive and Negative Syndrome Scale (PANSS). DRD2 mRNA levels in PBLs of acute schizophrenia patients, chronic schizophrenia patients, and healthy controls were 0.32±0.13, 0.37±0.19, and 0.34±0.09, respectively, and the difference was not significant. DAT mRNA levels in PBLs of the abovementioned groups were 0.48±0.24, 0.58±0.21 and 0.39±0.24, respectively (F = 4.330, P = 0.017), and comparisons between every group showed that DAT mRNA levels in PBLs of chronic schizophrenia patients were significantly higher than those in healthy controls (MS interclass = 0.198, p = 0.005). The correlation between DRD2 mRNA levels in PBLs and the positive symptom points of PANSS in acute schizophrenia patients was significant (r = 0.443, p = 0.044). In conclusion, DRD2 mRNA levels in PBLs are correlated with positive symptoms in acute schizophrenia patients, and DAT mRNA levels in PBLs of chronic schizophrenia patients are over-expressed.
Collapse
Affiliation(s)
- Liang Liu
- Clinical Psychiatry Department, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China
| | - Guozhen Yuan
- Clinical Psychiatry Department, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China
| | - Zaohuo Cheng
- Clinical Psychiatry Department, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China
- * E-mail:
| | - Guofu Zhang
- Clinical Psychiatry Department, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China
| | - Xiaowei Liu
- Clinical Psychiatry Department, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China
| | - Huifang Zhang
- Clinical Psychiatry Department, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China
| |
Collapse
|
|
27
|
Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving AKT1 that are corrected by antipsychotic medication. Int J Neuropsychopharmacol 2013; 16:1483-503. [PMID: 23442539 DOI: 10.1017/s1461145713000035] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Distinct gene expression profiles can be detected in peripheral blood mononuclear cells (PBMCs) in patients with schizophrenia; however, little is known about the effects of antipsychotic medication. This study compared gene expression profiles in PMBCs from treatment-naive patients with schizophrenia before and after antipsychotic drug treatment. PBMCs were obtained from 10 treatment-naive schizophrenia patients before and 6 wk after initiating antipsychotic drug treatment and compared to PMBCs collected from 11 healthy community volunteers. Genome-wide expression profiling was conducted using Illumina HumanHT-12 expression bead arrays and analysed using significance analysis of microarrays. This analysis identified 624 genes with altered expression (208 up-regulated, 416 down-regulated) prior to antipsychotic treatment (p < 0.05) including schizophrenia-associated genes AKT1, DISC1 and DGCR6. After 6-8 wk treatment of patients with risperidone or risperidone in combination with haloperidol, only 106 genes were altered, suggesting that the treatment corrected the expression of a large proportion of genes back to control levels. However, 67 genes continued to show the same directional change in expression after treatment. Ingenuity® pathway analysis and gene set enrichment analysis implicated dysregulation of biological functions and pathways related to inflammation and immunity in patients with schizophrenia. A number of the top canonical pathways dysregulated in treatment-naive patients signal through AKT1 that was up-regulated. After treatment, AKT1 returned to control levels and less dysregulation of these canonical pathways was observed. This study supports immune dysfunction and pathways involving AKT1 in the aetiopathophysiology of schizophrenia and their response to antipsychotic medication.
Collapse
|
|
28
|
Chana G, Bousman CA, Money TT, Gibbons A, Gillett P, Dean B, Everall IP. Biomarker investigations related to pathophysiological pathways in schizophrenia and psychosis. Front Cell Neurosci 2013; 7:95. [PMID: 23805071 PMCID: PMC3693064 DOI: 10.3389/fncel.2013.00095] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 06/03/2013] [Indexed: 12/28/2022] Open
Abstract
Post-mortem brain investigations of schizophrenia have generated swathes of data in the last few decades implicating candidate genes and protein. However, the relation of these findings to peripheral biomarker indicators and symptomatology remain to be elucidated. While biomarkers for disease do not have to be involved with underlying pathophysiology and may be largely indicative of diagnosis or prognosis, the ideal may be a biomarker that is involved in underlying disease processes and which is therefore more likely to change with progression of the illness as well as potentially being more responsive to treatment. One of the main difficulties in conducting biomarker investigations for major psychiatric disorders is the relative inconsistency in clinical diagnoses between disorders such as bipolar and schizophrenia. This has led some researchers to investigate biomarkers associated with core symptoms of these disorders, such as psychosis. The aim of this review is to evaluate the contribution of post-mortem brain investigations to elucidating the pathophysiology pathways involved in schizophrenia and psychosis, with an emphasis on major neurotransmitter systems that have been implicated. This data will then be compared to functional neuroimaging findings as well as findings from blood based gene expression investigations in schizophrenia in order to highlight the relative overlap in pathological processes between these different modalities used to elucidate pathogenesis of schizophrenia. In addition we will cover some recent and exciting findings demonstrating microRNA (miRNA) dysregulation in both the blood and the brain in patients with schizophrenia. These changes are pertinent to the topic due to their known role in post-transcriptional modification of gene expression with the potential to contribute or underlie gene expression changes observed in schizophrenia. Finally, we will discuss how post-mortem studies may aid future biomarker investigations.
Collapse
Affiliation(s)
- Gursharan Chana
- Department of Psychiatry, Melbourne Brain Centre, The University of Melbourne Parkville, VIC, Australia
| | | | | | | | | | | | | |
Collapse
|
|
29
|
Szuts V, Ménesi D, Varga-Orvos Z, Zvara Á, Houshmand N, Bitay M, Bogáts G, Virág L, Baczkó I, Szalontai B, Geramipoor A, Cotella D, Wettwer E, Ravens U, Deák F, Puskás LG, Papp JG, Kiss I, Varró A, Jost N. Altered expression of genes for Kir ion channels in dilated cardiomyopathy. Can J Physiol Pharmacol 2013; 91:648-56. [PMID: 23889090 DOI: 10.1139/cjpp-2012-0413] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Dilated cardiomyopathy (DCM) is a multifactorial disease characterized by left ventricular dilation that is associated with systolic dysfunction and increased action potential duration. The Kir2.x K⁺ channels (encoded by KCNJ genes) regulate the inward rectifier current (IK1) contributing to the final repolarization in cardiac muscle. Here, we describe the transitions in the gene expression profiles of 4 KCNJ genes from healthy or dilated cardiomyopathic human hearts. In the healthy adult ventricles, KCNJ2, KCNJ12, and KCNJ4 (Kir2.1-2.3, respectively) genes were expressed at high levels, while expression of the KCNJ14 (Kir2.4) gene was low. In DCM ventricles, the levels of Kir2.1 and Kir2.3 were upregulated, but those of Kir2.2 channels were downregulated. Additionally, the expression of the DLG1 gene coding for the synapse-associated protein 97 (SAP97) anchoring molecule exhibited a 2-fold decline with increasing age in normal hearts, and it was robustly downregulated in young DCM patients. These adaptations could offer a new aspect for the explanation of the generally observed physiological and molecular alterations found in DCM.
Collapse
Affiliation(s)
- Viktoria Szuts
- Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Kumarasinghe N, Tooney PA, Schall U. Finding the needle in the haystack: a review of microarray gene expression research into schizophrenia. Aust N Z J Psychiatry 2012; 46:598-610. [PMID: 22441207 DOI: 10.1177/0004867412442405] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND With an estimated 80% heritability, molecular genetic research into schizophrenia has remained inconclusive. Recent large-scale, genome-wide association studies only identified a small number of susceptibility genes with individually very small effect sizes. However, the variable expression of the phenotype is not well captured in diagnosis-based research as well as when assuming a 'heterogenic risk model' (as apposed to a monogenic or polygenic model). Hence, the expression of susceptibility genes in response to environmental factors in concert with other disease-promoting or protecting genes has increasingly attracted attention. METHOD The current review summarises findings of microarray gene expression research with relevance to schizophrenia as they emerged over the past decade. RESULTS Most findings from post mortem, peripheral tissues and animal models to date have linked altered gene expression in schizophrenia to presynaptic function, signalling, myelination, neural migration, cellular immune mechanisms, and response to oxidative stress consistent with multiple small effects of many individual genes. However, the majority of results are difficult to interpret due to small sample sizes (i.e. potential type-2 errors), confounding factors (i.e. medication effects) or lack of plausible neurobiological theory. CONCLUSION Nevertheless, microarray gene expression research is likely to play an important role in the future when investigating gene/gene and gene/environment interactions by adopting a neurobiologically sound theoretical framework.
Collapse
Affiliation(s)
- Nishantha Kumarasinghe
- Priority Centre for Translational Neuroscience and Mental Health Research, University of Newcastle, Callaghan, Australia
| | | | | |
Collapse
|
|
31
|
Increase in dopaminergic, but not serotoninergic, receptors in T-cells as a marker for schizophrenia severity. J Psychiatr Res 2012; 46:738-42. [PMID: 22497994 DOI: 10.1016/j.jpsychires.2012.03.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2011] [Revised: 02/10/2012] [Accepted: 03/02/2012] [Indexed: 11/22/2022]
Abstract
Schizophrenia is characterized by a slow deteriorating mental illness. Although the pathophysiology mechanisms are not fully understood, different studies have suggested a role for the immune system in the pathogenesis of schizophrenia. To date, an altered expression or signaling of neurotransmitters receptors is observed in immune cells during psychiatric disorders. In the present study, we investigated the expression of different serotonin and dopamine receptors in T-cells of schizophrenic and control patients. We used flow cytometry to determine the pattern of expression of dopamine (D2 and D4) and serotonine receptors (SR1A, SR1C, SR2A, SR2B), as well as serotonin transporter (ST), in T-cell subsets (CD4 and CD8). Expression of serotonin receptors and ST in T-cells of schizophrenic patients were not different from controls. However, the percentages of CD4+D4+ and CD8+D4+ were increased in schizophrenic patients as compared to controls. In addition, increased percentages of CD8+D2+ cells were also observed in schizophrenic patients, albeit this population revealed lower CD4+D2+ cells in comparison to controls. Interestingly, a relationship between clinical symptoms and immunological parameters was also observed. We showed that the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were positively related to CD8+D2+ cells, though AIMS was inversely related to CD4+D4+ cells. In conclusion, the alteration in the pattern of cell population and molecules expressed by them might serve as a promising biomarker for diagnosis of schizophrenia.
Collapse
|
|
32
|
Wirgenes KV, Sønderby IE, Haukvik UK, Mattingsdal M, Tesli M, Athanasiu L, Sundet K, Røssberg JI, Dale AM, Brown AA, Agartz I, Melle I, Djurovic S, Andreassen OA. TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders. Transl Psychiatry 2012; 2:e112. [PMID: 22832956 PMCID: PMC3365258 DOI: 10.1038/tp.2012.39] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 03/29/2012] [Accepted: 04/05/2012] [Indexed: 12/21/2022] Open
Abstract
TCF4 is involved in neurodevelopment, and intergenic and intronic variants in or close to the TCF4 gene have been associated with susceptibility to schizophrenia. However, the functional role of TCF4 at the level of gene expression and relationship to severity of core psychotic phenotypes are not known. TCF4 mRNA expression level in peripheral blood was determined in a large sample of patients with psychosis spectrum disorders (n = 596) and healthy controls (n = 385). The previously identified TCF4 risk variants (rs12966547 (G), rs9960767 (C), rs4309482 (A), rs2958182 (T) and rs17512836 (C)) were tested for association with characteristic psychosis phenotypes, including neurocognitive traits, psychotic symptoms and structural magnetic resonance imaging brain morphometric measures, using a linear regression model. Further, we explored the association of additional 59 single nucleotide polymorphisms (SNPs) covering the TCF4 gene to these phenotypes. The rs12966547 and rs4309482 risk variants were associated with poorer verbal fluency in the total sample. There were significant associations of other TCF4 SNPs with negative symptoms, verbal learning, executive functioning and age at onset in psychotic patients and brain abnormalities in total sample. The TCF4 mRNA expression level was significantly increased in psychosis patients compared with controls and positively correlated with positive- and negative-symptom levels. The increase in TCF4 mRNA expression level in psychosis patients and the association of TCF4 SNPs with core psychotic phenotypes across clinical, cognitive and brain morphological domains support that common TCF4 variants are involved in psychosis pathology, probably related to abnormal neurodevelopment.
Collapse
Affiliation(s)
- K V Wirgenes
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Yin DM, Chen YJ, Sathyamurthy A, Xiong WC, Mei L. Synaptic dysfunction in schizophrenia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 970:493-516. [PMID: 22351070 DOI: 10.1007/978-3-7091-0932-8_22] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Schizophrenia alters basic brain processes of perception, emotion, and judgment to cause hallucinations, delusions, thought disorder, and cognitive deficits. Unlike neurodegeneration diseases that have irreversible neuronal degeneration and death, schizophrenia lacks agreeable pathological hallmarks, which makes it one of the least understood psychiatric disorders. With identification of schizophrenia susceptibility genes, recent studies have begun to shed light on underlying pathological mechanisms. Schizophrenia is believed to result from problems during neural development that lead to improper function of synaptic transmission and plasticity, and in agreement, many of the susceptibility genes encode proteins critical for neural development. Some, however, are also expressed at high levels in adult brain. Here, we will review evidence for altered neurotransmission at glutamatergic, GABAergic, dopaminergic, and cholinergic synapses in schizophrenia and discuss roles of susceptibility genes in neural development as well as in synaptic plasticity and how their malfunction may contribute to pathogenic mechanisms of schizophrenia. We propose that mouse models with precise temporal and spatial control of mutation or overexpression would be useful to delineate schizophrenia pathogenic mechanisms.
Collapse
Affiliation(s)
- Dong-Min Yin
- Department of Neurology, Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA 30912, USA
| | | | | | | | | |
Collapse
|
|
34
|
Sequeira PA, Martin MV, Vawter MP. The first decade and beyond of transcriptional profiling in schizophrenia. Neurobiol Dis 2012; 45:23-36. [PMID: 21396449 PMCID: PMC3178722 DOI: 10.1016/j.nbd.2011.03.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2010] [Revised: 02/28/2011] [Accepted: 03/02/2011] [Indexed: 01/19/2023] Open
Abstract
Gene expression changes in brains of individuals with schizophrenia (SZ) have been hypothesized to reflect possible pathways related to pathophysiology and/or medication. Other factors having robust effects on gene expression profiling in brain and possibly influence the schizophrenia transcriptome such as age and pH are examined. Pathways of curated gene expression or gene correlation networks reported in SZ (white matter, apoptosis, neurogenesis, synaptic plasticity, glutamatergic and GABAergic neurotransmission, immune and stress-response, mitochondrial, and neurodevelopment) are not unique to SZ and have been associated with other psychiatric disorders. Suggestions going forward to improve the next decade of profiling: consider multiple brain regions that are carefully dissected, release large datasets from multiple brain regions in controls to better understand neurocircuitry, integrate genetics and gene expression, measure expression variants on genome wide level, peripheral biomarker studies, and analyze the transcriptome across a developmental series of brains. Gene expression, while an important feature of the genomic landscape, requires further systems biology to advance from control brains to a more precise definition of the schizophrenia interactome.
Collapse
Affiliation(s)
- P. Adolfo Sequeira
- Functional Genomics Laboratory Department of Psychiatry and Human Behavior School of Medicine University of California, Irvine Irvine CA 92697-4260 (949) 824-9014
| | - Maureen V. Martin
- Functional Genomics Laboratory Department of Psychiatry and Human Behavior School of Medicine University of California, Irvine Irvine CA 92697-4260 (949) 824-9014
| | - Marquis P. Vawter
- Functional Genomics Laboratory Department of Psychiatry and Human Behavior School of Medicine University of California, Irvine Irvine CA 92697-4260 (949) 824-9014
| |
Collapse
|
|
35
|
Glatt SJ, Stone WS, Nossova N, Liew CC, Seidman LJ, Tsuang MT. Similarities and differences in peripheral blood gene-expression signatures of individuals with schizophrenia and their first-degree biological relatives. Am J Med Genet B Neuropsychiatr Genet 2011; 156B:869-87. [PMID: 21972136 PMCID: PMC3213682 DOI: 10.1002/ajmg.b.31239] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Accepted: 08/31/2011] [Indexed: 01/13/2023]
Abstract
Several studies have evaluated the potential utility of blood-based whole-transcriptome signatures as a source of biomarkers for schizophrenia. This endeavor has been complicated by the fact that individuals with schizophrenia typically differ from appropriate comparison subjects on more than just the presence of the disorder; for example, individuals with schizophrenia typically receive antipsychotic medications, and have been dealing with the sequelae of this chronic illness for years. The inability to control such factors introduces a considerable degree of uncertainty in the results to date. To overcome this, we performed a blood-based gene-expression profiling study of schizophrenia patients (n = 9) as well as their unmedicated, nonpsychotic, biological siblings (n = 9) and unaffected comparison subjects (n = 12). The unaffected biological siblings, who may harbor some of the genetic predisposition to schizophrenia, exhibited a host of gene-expression differences from unaffected comparison subjects, many of which were shared by their schizophrenic siblings, perhaps indicative of underlying risk factors for the disorder. Several genes that were dysregulated in both individuals with schizophrenia and their siblings related to nucleosome and histone structure and function, suggesting a potential epigenetic mechanism underlying the risk state for the disorder. Nonpsychotic siblings also displayed some differences from comparison subjects that were not found in their affected siblings, suggesting that the dysregulation of some genes in peripheral blood may be indicative of underlying protective factors. This study, while exploratory, illustrated the potential utility and increased informativeness of including unaffected first-degree relatives in research in pursuit of peripheral biomarkers for schizophrenia.
Collapse
Affiliation(s)
- Stephen J. Glatt
- Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab); Departments of Psychiatry and Behavioral Sciences & Neuroscience and Physiology; Medical Genetics Research Center; SUNY Upstate Medical University; Syracuse, NY; U.S.A.,To whom correspondence should be addressed: SUNY Upstate Medical University, 750 East Adams Street, Weiskotten Hall, Room 3283, Syracuse, NY 13210, U.S.A., , Facsimile: (315) 464-7744, Telephone: (315) 464-7742
| | - William S. Stone
- Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center; Department of Psychiatry; Harvard Medical School; Boston, MA; U.S.A.,Harvard Institute of Psychiatric Epidemiology and Genetics; Departments of Epidemiology and Psychiatry; Harvard School of Public Health and Harvard Medical School; Boston, MA; U.S.A
| | - Nadine Nossova
- Research Department; GeneNews Ltd; Richmond Hill, Ontario; Canada
| | - Choong-Chin Liew
- Research Department; GeneNews Ltd; Richmond Hill, Ontario; Canada
| | - Larry J. Seidman
- Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center; Department of Psychiatry; Harvard Medical School; Boston, MA; U.S.A.,Harvard Institute of Psychiatric Epidemiology and Genetics; Departments of Epidemiology and Psychiatry; Harvard School of Public Health and Harvard Medical School; Boston, MA; U.S.A
| | - Ming T. Tsuang
- Harvard Institute of Psychiatric Epidemiology and Genetics; Departments of Epidemiology and Psychiatry; Harvard School of Public Health and Harvard Medical School; Boston, MA; U.S.A.,Center for Behavioral Genomics; Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive; La Jolla, CA 92039; U.S.A.,Veterans Affairs San Diego Healthcare System; 3350 La Jolla Village Drive; San Diego, CA 92161; U.S.A
| |
Collapse
|
|
36
|
Gui YX, Wan Y, Xiao Q, Wang Y, Wang G, Chen SD. Verification of expressions of Kir2 as potential peripheral biomarkers in lymphocytes from patients with Parkinson's disease. Neurosci Lett 2011; 505:104-8. [PMID: 22001575 DOI: 10.1016/j.neulet.2011.09.070] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 09/20/2011] [Accepted: 09/30/2011] [Indexed: 10/16/2022]
Abstract
Prior studies have reported gene expression alterations in peripheral blood lymphocytes (PBLs) obtained from patients with Parkinson's disease (PD) as compared to healthy controls. These alterations can not only be regarded as potential biomarkers, but also enhance understanding of the pathogenic mechanism of PD. In the present study, the gene expression levels of dopamine receptor (D2, D3), inward rectified potassium channels subunits Kir2 (Kir2.1, Kir2.2, Kir2.3, Kir2.4) and ATP-sensitive potassium channel subunit Kir6.2 in PBLs were analyzed using quantitative real-time PCR among 20 PD patients with medication, 10 PD patients without medication and 16 healthy controls, respectively. The results showed that there was a significantly decrease of the D2, D3 mRNA expression in PBLs of PD patients compared with that in healthy controls. The four inward rectified potassium channels Kir2.1, Kir2.2, Kir2.3, and Kir2.4 mRNA expression in PBLs from PD patients were also significantly down-regulated than that from age-matched healthy controls. However, there was no apparent difference in expression of another potassium channel Kir6.2 mRNA between PD patients and healthy controls. We proposed that the Kir2 potassium channels mRNA on blood lymphocytes may be regarded as a potential biomarker for PD screening.
Collapse
Affiliation(s)
- Ya-Xing Gui
- Department of Neurology & Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | | | | | | | | | | |
Collapse
|
|
37
|
Woelk CH, Singhania A, Pérez-Santiago J, Glatt SJ, Tsuang MT. The utility of gene expression in blood cells for diagnosing neuropsychiatric disorders. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2011; 101:41-63. [PMID: 22050848 DOI: 10.1016/b978-0-12-387718-5.00003-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Objective diagnostic tools are required for neuropsychiatric disorders. Gene expression in blood cells may provide such a tool and has already been used to construct classifiers capable of diagnosing many human diseases. This chapter discusses the use of microarray gene expression data to construct diagnostic classifiers for neuropsychiatric disorders. The potential pitfalls of microarray gene expression analysis and the experimental design and methods suitable for classifier construction are described in detail. A review of studies that have analyzed gene expression in blood cells from patients with neuropsychiatric disorders is presented with an emphasis on the feasibility of generating a diagnostic classifier for schizophrenia. Finally, the future directions of the field are discussed with respect to using blood gene expression to tailor antipsychotic medications to individual patients, applying microRNA expression for diagnostic purposes, as well as the implications of next-generation sequencing technologies for gene expression analysis.
Collapse
Affiliation(s)
- Christopher H Woelk
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | | | | | | | | |
Collapse
|
|
38
|
Olincy A, House R, Gao B, Recksiek P, Phang TL, Sullivan B, Hollis JP, Hopkins J, Shade T, Edwards MG, Vianzon R, Griffiths C, Ceilley J, Helfrich RW, Ritvo J, Weis E, Weiss D, Gault J. Elevated DISC1 transcript levels in PBMCs during acute psychosis in patients with schizophrenia. TRANSLATIONAL BIOMEDICINE 2011; 2:183. [PMID: 22319686 PMCID: PMC3272882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
BACKGROUND: Severe mental disorders like schizophrenia are a leading cause of disability in people in the prime years of their lives (aged 15 to 44 years). Relapse is a primary contributor to schizophrenia disease burden and is frequently attributed to medication noncompliance and inadequate doses. Currently, a patient's neuroleptic dose is titrated to clinical response within recommended dose ranges. Use of unbiased biomarkers of effective neuroleptic treatment-response would greatly facilitate the identification of a person's lowest effective dose to minimize unsafe side effects and improve compliance. Biomarkers may allow precisely tailored adjustments of neuroleptic dose to reduce relapse due to variable disease course. METHODS AND FINDINGS: Biomarkers of active psychosis were sought among persons with schizophrenia hospitalized with acute psychosis. The transcriptional response of peripheral blood mononuclear cells (PBMCs) to treatment of psychosis was measured using RNA expression profiling in 12-paired samples from patients with schizophrenia. The paired samples were collected early after treatment initiation and again just before patients were released from the hospital. Patients showed significant improvement in positive symptoms of psychosis assessed at each sample collection using a brief psychiatric rating scale (BPRS) (P<0.05). Preliminary evidence is presented indicating that decreased transcript levels of isoforms of disrupted in schizophrenia 1 (DISC1) measured in PBMCs were associated with treatment in 91% of samples (P=0.037). CONCLUSION: Further studies are warranted to identify neuroleptic-response biomarkers and to replicate this initial finding of association of DISC1 transcript levels with treatment of psychosis.
Collapse
Affiliation(s)
- Ann Olincy
- Department of Psychiatry, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Robert House
- Behavioral Health, Denver Health Medical Center, Denver, CO, USA
| | - Bifeng Gao
- Cancer Center, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Peter Recksiek
- Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Tzu Lip Phang
- Department of Pulmonary Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Bernadette Sullivan
- Department of Psychiatry, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Jeff P. Hollis
- Department of Psychiatry, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Janet Hopkins
- Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Ted Shade
- Cancer Center, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Michael G Edwards
- Department of Pulmonary Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Ruby Vianzon
- Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Cory Griffiths
- Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - John Ceilley
- Behavioral Health, Denver Health Medical Center, Denver, CO, USA
| | | | - Jonathan Ritvo
- Behavioral Health, Denver Health Medical Center, Denver, CO, USA
| | - Erica Weis
- Behavioral Health, Denver Health Medical Center, Denver, CO, USA
| | - David Weiss
- Behavioral Health, Denver Health Medical Center, Denver, CO, USA
| | - Judith Gault
- Department of Psychiatry, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
- Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| |
Collapse
|
|
39
|
Kurian SM, Le-Niculescu H, Patel SD, Bertram D, Davis J, Dike C, Yehyawi N, Lysaker P, Dustin J, Caligiuri M, Lohr J, Lahiri DK, Nurnberger JI, Faraone SV, Geyer MA, Tsuang MT, Schork NJ, Salomon DR, Niculescu AB. Identification of blood biomarkers for psychosis using convergent functional genomics. Mol Psychiatry 2011; 16:37-58. [PMID: 19935739 DOI: 10.1038/mp.2009.117] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.
Collapse
Affiliation(s)
- S M Kurian
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Takahashi M, Hayashi H, Watanabe Y, Sawamura K, Fukui N, Watanabe J, Kitajima T, Yamanouchi Y, Iwata N, Mizukami K, Hori T, Shimoda K, Ujike H, Ozaki N, Iijima K, Takemura K, Aoshima H, Someya T. Diagnostic classification of schizophrenia by neural network analysis of blood-based gene expression signatures. Schizophr Res 2010; 119:210-8. [PMID: 20083392 DOI: 10.1016/j.schres.2009.12.024] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2009] [Revised: 12/12/2009] [Accepted: 12/20/2009] [Indexed: 12/20/2022]
Abstract
Gene expression profiling with microarray technology suggests that peripheral blood cells might be a surrogate for postmortem brain tissue in studies of schizophrenia. The development of an accessible peripheral biomarker would substantially help in the diagnosis of this disease. We used a bioinformatics approach to examine whether the gene expression signature in whole blood contains enough information to make a specific diagnosis of schizophrenia. Unpaired t-tests of gene expression datasets from 52 antipsychotics-free schizophrenia patients and 49 normal controls identified 792 differentially expressed probes. Functional profiling with DAVID revealed that eleven of these genes were previously reported to be associated with schizophrenia, and 73 of them were expressed in the brain tissue. We analyzed the datasets with one of the supervised classifiers, artificial neural networks (ANNs). The samples were subdivided into training and testing sets. Quality filtering and stepwise forward selection identified 14 probes as predictors of the diagnosis. ANNs were then trained with the selected probes as the input and the training set for known diagnosis as the output. The constructed model achieved 91.2% diagnostic accuracy in the training set and 87.9% accuracy in the hold-out testing set. On the other hand, hierarchical clustering, a standard but unsupervised classifier, failed to separate patients and controls. These results suggest analysis of a blood-based gene expression signature with the supervised classifier, ANNs, might be a diagnostic tool for schizophrenia.
Collapse
Affiliation(s)
- Makoto Takahashi
- Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi-dori 1-757, Niigata 951-8510, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Bousman CA, Chana G, Glatt SJ, Chandler SD, Lucero GR, Tatro E, May T, Lohr JB, Kremen WS, Tsuang MT, Everall IP. Preliminary evidence of ubiquitin proteasome system dysregulation in schizophrenia and bipolar disorder: convergent pathway analysis findings from two independent samples. Am J Med Genet B Neuropsychiatr Genet 2010; 153B:494-502. [PMID: 19582768 PMCID: PMC4165610 DOI: 10.1002/ajmg.b.31006] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Schizophrenia (SCZ) and bipolar disorder (BPD) are polygenic disorders with many genes contributing to their etiologies. The aim of this investigation was to search for dysregulated molecular and cellular pathways for these disorders as well as psychosis. We conducted a blood-based microarray investigation in two independent samples with SCZ and BPD from San Diego (SCZ = 13, BPD = 9, control = 8) and Taiwan (SCZ = 11, BPD = 14, control = 16). Diagnostic groups were compared to controls, and subjects with a history of psychosis [PSYCH(+): San Diego (n = 6), Taiwan (n = 14)] were compared to subjects without such history [PSYCH(-): San Diego (n = 11), Taiwan (n = 14)]. Analyses of covariance comparing mean expression levels on a gene-by-gene basis were conducted to generate the top 100 significantly dysregulated gene lists for both samples by each diagnostic group. Gene lists were imported into Ingenuity Pathway Analysis (IPA) software. Results showed the ubiquitin proteasome pathway (UPS) was listed in the top ten canonical pathways for BPD and psychosis diagnostic groups across both samples with a considerably low likelihood of a chance occurrence (P = 0.001). No overlap in dysregulated genes populating these pathways was observed between the two independent samples. Findings provide preliminary evidence of UPS dysregulation in BPD and psychosis as well as support further investigation of the UPS and other molecular and cellular pathways for potential biomarkers for SCZ, BPD, and/or psychosis.
Collapse
Affiliation(s)
- Chad A. Bousman
- Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, California
| | - Gursharan Chana
- Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, California
| | - Stephen J. Glatt
- Department of Psychiatry and Behavioral Sciences, Medical Genetics Research Center, SUNY Upstate Medical University, Syracuse, New York
| | - Sharon D. Chandler
- Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, California
| | - Ginger R. Lucero
- Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, California
| | - Erick Tatro
- Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, California
| | - Todd May
- Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, California
| | - James B. Lohr
- Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, California
| | - William S. Kremen
- Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, California,Veterans Affairs San Diego Healthcare System, San Diego, California
| | - Ming T. Tsuang
- Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, California,Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard Departments of Epidemiology and Psychiatry, Boston, Massachusetts,Veterans Affairs San Diego Healthcare System, San Diego, California
| | - Ian P. Everall
- Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, California,Correspondence to: Ian P. Everall, M.D., Ph.D., Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92039.
| |
Collapse
|
|
42
|
Kuzman MR, Medved V, Terzic J, Krainc D. Genome-wide expression analysis of peripheral blood identifies candidate biomarkers for schizophrenia. J Psychiatr Res 2009; 43:1073-7. [PMID: 19358997 DOI: 10.1016/j.jpsychires.2009.03.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2008] [Revised: 02/09/2009] [Accepted: 03/13/2009] [Indexed: 12/16/2022]
Abstract
The aim of this study was to analyze gene expression in blood of patients with newly-diagnosed schizophrenia during their first psychotic episode and subsequent remission. Whole blood samples were obtained from 32 untreated patients presenting with their first psychotic episode suggestive of schizophrenia and 32 age- and gender-matched controls. Using Affymetrix micoarrays, we identified significantly altered expression of 180 gene probes in psychotic patients compared to controls. A subset of four significantly changed genes was further confirmed with QRT-PCR. The following genes were significantly altered in patients: glucose transporter, SLC2A3 (p<0.001) and actin assembly factor DAAM2 (p<0.001) were increased, whereas translation, zinc metallopeptidase, neurolysin 1 and myosin C were significantly decreased (p<0.05). Expression of these candidate markers was also analyzed in a longitudinal study (12-24 months) in 12 patients who achieved full remission. Interestingly, expression of DAAM2 returned to control levels in patients who were in remission after their first psychotic episode, suggesting that its expression correlates with diseases progression and/or response to treatment. In summary, we identified changes of gene expression from peripheral blood which might help discriminate patients with schizophrenia from controls. While these results are promising, especially for DAAM2 whose polymorphic variants have been found significantly associated with schizophrenia, it will be important to analyze larger cohorts of patients in order to firmly establish changes in gene expression as blood markers of schizophrenia.
Collapse
Affiliation(s)
- Martina Rojnic Kuzman
- Department of Psychiatry, Zagreb University Hospital Centre and Zagreb School of Medicine, Zagreb, Croatia.
| | | | | | | |
Collapse
|
|
43
|
Glatt S, Chandler S, Bousman C, Chana G, Lucero G, Tatro E, May T, Lohr J, Kremen W, Everall I, Tsuang M. Alternatively Spliced Genes as Biomarkers for Schizophrenia, Bipolar Disorder and Psychosis: A Blood-Based Spliceome-Profiling Exploratory Study. CURRENT PHARMACOGENOMICS AND PERSONALIZED MEDICINE 2009; 7:164-188. [PMID: 21532980 PMCID: PMC3083864 DOI: 10.2174/1875692110907030164] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
OBJECTIVE: Transcriptomic biomarkers of psychiatric diseases obtained from a query of peripheral tissues that are clinically accessible (e.g., blood cells instead of post-mortem brain tissue) have substantial practical appeal to discern the molecular subtypes of common complex diseases such as major psychosis. To this end, spliceome-profiling is a new methodological approach that has considerable conceptual relevance for discovery and clinical translation of novel biomarkers for psychiatric illnesses. Advances in microarray technology now allow for improved sensitivity in measuring the transcriptome while simultaneously querying the "exome" (all exons) and "spliceome" (all alternatively spliced variants). The present study aimed to evaluate the feasibility of spliceome-profiling to discern transcriptomic biomarkers of psychosis. METHODS: We measured exome and spliceome expression in peripheral blood mononuclear cells from 13 schizophrenia patients, nine bipolar disorder patients, and eight healthy control subjects. Each diagnostic group was compared to each other, and the combined group of bipolar disorder and schizophrenia patients was also compared to the control group. Furthermore, we compared subjects with a history of psychosis to subjects without such history. RESULTS: After applying Bonferroni corrections for the 21,866 full-length gene transcripts analyzed, we found significant interactions between diagnostic group and exon identity, consistent with group differences in rates or types of alternative splicing. Relative to the control group, 18 genes in the bipolar disorder group, eight genes in the schizophrenia group, and 15 genes in the combined bipolar disorder and schizophrenia group appeared differentially spliced. Importantly, thirty-three genes showed differential splicing patterns between the bipolar disorder and schizophrenia groups. More frequent exon inclusion and/or over-expression was observed in psychosis. Finally, these observations are reconciled with an analysis of the ontologies, the pathways and the protein domains significantly over-represented among the alternatively spliced genes, several of which support prior discoveries. CONCLUSIONS: To our knowledge, this is the first blood-based spliceome-profiling study of schizophrenia and bipolar disorder to be reported. The battery of alternatively spliced genes and exons identified in this discovery-oriented exploratory study, if replicated, may have potential utility to discern the molecular subtypes of psychosis. Spliceome-profiling, as a new methodological approach in transcriptomics, warrants further work to evaluate its utility in personalized medicine. Potentially, this approach could also permit the future development of tissue-sampling methodologies in a form that is more acceptable to patients and thereby allow monitoring of dynamic and time-dependent plasticity in disease severity and response to therapeutic interventions in clinical psychiatry.
Collapse
Affiliation(s)
- S.J. Glatt
- Department of Psychiatry and Behavioral Sciences, and Medical Genetics Research Center; SUNY Upstate Medical University; 750 East Adams Street; Syracuse, NY, 13210; USA
| | - S.D. Chandler
- Center for Behavioral Genomics; Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive; La Jolla, CA 92039; USA
| | - C.A. Bousman
- Center for Behavioral Genomics; Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive; La Jolla, CA 92039; USA
| | - G. Chana
- Center for Behavioral Genomics; Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive; La Jolla, CA 92039; USA
| | - G.R. Lucero
- Center for Behavioral Genomics; Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive; La Jolla, CA 92039; USA
| | - E. Tatro
- Center for Behavioral Genomics; Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive; La Jolla, CA 92039; USA
| | - T. May
- Center for Behavioral Genomics; Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive; La Jolla, CA 92039; USA
| | - J.B. Lohr
- Center for Behavioral Genomics; Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive; La Jolla, CA 92039; USA
| | - W.S. Kremen
- Center for Behavioral Genomics; Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive; La Jolla, CA 92039; USA
- Veterans Affairs San Diego Healthcare System; 3350 La Jolla Village Drive; San Diego, CA 92161; USA
| | - I.P. Everall
- Center for Behavioral Genomics; Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive; La Jolla, CA 92039; USA
| | - M.T. Tsuang
- Center for Behavioral Genomics; Department of Psychiatry; University of California, San Diego; 9500 Gilman Drive; La Jolla, CA 92039; USA
- Veterans Affairs San Diego Healthcare System; 3350 La Jolla Village Drive; San Diego, CA 92161; USA
- Harvard Institute of Psychiatric Epidemiology and Genetics; Harvard Departments of Epidemiology and Psychiatry; 25 Shattuck Street; Boston, MA 02115; USA
| |
Collapse
|
|
44
|
Kirillova GP, Hrutkay RJ, Shurin MR, Shurin GV, Tourkova IL, Vanyukov MM. Dopamine receptors in human lymphocytes: radioligand binding and quantitative RT-PCR assays. J Neurosci Methods 2008; 174:272-80. [PMID: 18721826 PMCID: PMC2637390 DOI: 10.1016/j.jneumeth.2008.07.018] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2008] [Revised: 07/22/2008] [Accepted: 07/22/2008] [Indexed: 10/21/2022]
Abstract
Analysis of dopamine receptors (DR) in lymphocytes of the human peripheral blood mononuclear cell (PBMC) fraction is an attractive tool for evaluation of functional properties of dopaminergic function underlying variation in complex psychological/psychopathological traits. Receptor binding assays (RBAs) with selective radioligands, which are widely used in CNS studies, have not produced consistent results when applied to isolated PBMC. We tested the assay conditions that could be essential for detection of DR in human PBMC and their membrane preparations. Using [(3)H]SCH23390, a dopamine D1-like receptor antagonist, we demonstrated the presence of two binding sites in PBMC-derived membrane fraction. One of them is characterized by the K(d) value consistent with that reported for D5 dopamine receptors in human lymphocytes, whereas the other K(d) value possibly corresponds to serotonin receptor(s). Although D5 receptor binding sites in PBMC membranes could be characterized by binding assays, the low protein expression and the large volume of blood needed for membrane preparation render the binding method impracticable for individual phenotyping. In contrast, real-time RT-PCR may be used for this purpose, contingent on the relationship between DR expression in the brain and in lymphocytes. The expression of the DRD2-DRD5 genes, as detected by this method, varied widely among samples, whereas the DRD1 expression was not detected. The expression levels were comparable with those in the brain for DRD3 and DRD4, and were significantly lower for DRD2 and DRD5.
Collapse
Affiliation(s)
- Galina P Kirillova
- Center for Education and Drug Abuse Research, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | | | | | | | | | | |
Collapse
|
|
45
|
Kakiuchi C, Ishiwata M, Nanko S, Ozaki N, Iwata N, Umekage T, Tochigi M, Kohda K, Sasaki T, Imamura A, Okazaki Y, Kato T. Up-regulation of ADM and SEPX1 in the lymphoblastoid cells of patients in monozygotic twins discordant for schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2008; 147B:557-64. [PMID: 18081029 DOI: 10.1002/ajmg.b.30643] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The contribution of genetic factors to schizophrenia is well established and recent studies have indicated several strong candidate genes. However, the pathophysiology of schizophrenia has not been totally elucidated yet. To date, studies of monozygotic twins discordant for schizophrenia have provided insight into the pathophysiology of this illness; this type of study can exclude inter-individual variability and confounding factors such as effects of drugs. In this study we used DNA microarray analysis to examine the mRNA expression patterns in the lymphoblastoid (LB) cells derived from two pairs of monozygotic twins discordant for schizophrenia. From five independent replicates for each pair of twins, we selected five genes, which included adrenomedullin (ADM) and selenoprotein X1 (SEPX1), as significantly changed in both twins with schizophrenia. Interestingly, ADM was previously reported to be up-regulated in both the LB cells and plasma of schizophrenic patients, and SEPX1 was included in the list of genes up-regulated in the peripheral blood cells of schizophrenia patients by microarray analysis. Then, we performed a genetic association study of schizophrenia in the Japanese population and examined the copy number variations, but observed no association. These findings suggest the possible role of ADM and SEPX1 as biomarkers of schizophrenia. The results also support the usefulness of gene expression analysis in LB cells of monozygotic twins discordant for an illness.
Collapse
Affiliation(s)
- Chihiro Kakiuchi
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Yao Y, Schröder J, Karlsson H. Verification of proposed peripheral biomarkers in mononuclear cells of individuals with schizophrenia. J Psychiatr Res 2008; 42:639-43. [PMID: 17825842 DOI: 10.1016/j.jpsychires.2007.07.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2007] [Revised: 07/04/2007] [Accepted: 07/20/2007] [Indexed: 01/13/2023]
Abstract
Recent studies reported gene expression alterations in peripheral blood cells (PBC) obtained from patients with schizophrenia as compared to healthy controls. These alterations can not only be regarded as potential biomarkers but can also further our understanding of the disease. In light of previous reports, expression levels of the following genes: APOBEC3B, CXCL1, DRD2, GNAO1, Kir2.3, S100A9, and SELENBP1 in PBCs were compared between 30 first-hospitalized patients with schizophrenia and 26 healthy controls using quantitative real-time PCR. A significant elevation (2.6-fold; p<0.05) was confirmed for transcripts from the gene CXCL1 but not from the other genes investigated. Within the patients group, APOBEC3B expression was inversely correlated with duration of neuroleptic treatment. These findings indicate that gene expression in PBC from patients with schizophrenia may not only vary with the methods used for analysis but also with state-related differences in gene expression.
Collapse
Affiliation(s)
- Yuanrong Yao
- Department of Neurology, Tianjin Medical University General Hospital, Anshan Avenue 154, 300052 Tianjin, China
| | | | | |
Collapse
|
|
47
|
Le-Niculescu H, McFarland MJ, Ogden CA, Balaraman Y, Patel S, Tan J, Rodd ZA, Paulus M, Geyer MA, Edenberg HJ, Glatt SJ, Faraone SV, Nurnberger JI, Kuczenski R, Tsuang MT, Niculescu AB. Phenomic, convergent functional genomic, and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism. Am J Med Genet B Neuropsychiatr Genet 2008; 147B:134-66. [PMID: 18247375 DOI: 10.1002/ajmg.b.30707] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
We had previously identified the clock gene D-box binding protein (Dbp) as a potential candidate gene for bipolar disorder and for alcoholism, using a Convergent Functional Genomics (CFG) approach. Here we report that mice with a homozygous deletion of DBP have lower locomotor activity, blunted responses to stimulants, and gain less weight over time. In response to a chronic stress paradigm, these mice exhibit a diametric switch in these phenotypes. DBP knockout mice are also activated by sleep deprivation, similar to bipolar patients, and that activation is prevented by treatment with the mood stabilizer drug valproate. Moreover, these mice show increased alcohol intake following exposure to stress. Microarray studies of brain and blood reveal a pattern of gene expression changes that may explain the observed phenotypes. CFG analysis of the gene expression changes identified a series of novel candidate genes and blood biomarkers for bipolar disorder, alcoholism, and stress reactivity.
Collapse
Affiliation(s)
- H Le-Niculescu
- Laboratory of Neurophenomics, Indiana University School of Medicine, Indianapolis, Indiana
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Domenici E, Muglia P. The search for peripheral disease markers in psychiatry by genomic and proteomic approaches. ACTA ACUST UNITED AC 2007; 1:235-51. [DOI: 10.1517/17530059.1.2.235] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
|
|
49
|
Le-Niculescu H, Balaraman Y, Patel S, Tan J, Sidhu K, Jerome RE, Edenberg HJ, Kuczenski R, Geyer MA, Nurnberger JI, Faraone SV, Tsuang MT, Niculescu AB. Towards understanding the schizophrenia code: an expanded convergent functional genomics approach. Am J Med Genet B Neuropsychiatr Genet 2007; 144B:129-58. [PMID: 17266109 DOI: 10.1002/ajmg.b.30481] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Identifying genes for schizophrenia through classical genetic approaches has proven arduous. Here, we present a comprehensive convergent analysis that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a psychomimetic agent - phencyclidine (PCP), and an anti-psychotic - clozapine), with human genetic linkage data and human postmortem brain data, as a Bayesian strategy of cross validating findings. Topping the list of candidate genes, we have three genes involved in GABA neurotransmission (GABRA1, GABBR1, and GAD2), one gene involved in glutamate neurotransmission (GRIA2), one gene involved in neuropeptide signaling (TAC1), two genes involved in synaptic function (SYN2 and KCNJ4), six genes involved in myelin/glial function (CNP, MAL, MBP, PLP1, MOBP and GFAP), and one gene involved in lipid metabolism (LPL). These data suggest that schizophrenia is primarily a disorder of brain functional and structural connectivity, with GABA neurotransmission playing a prominent role. These findings may explain the EEG gamma band abnormalities detected in schizophrenia. The analysis also revealed other high probability candidates genes (neurotransmitter signaling, other structural proteins, ion channels, signal transduction, regulatory enzymes, neuronal migration/neurite outgrowth, clock genes, transcription factors, RNA regulatory genes), pathways and mechanisms of likely importance in pathophysiology. Some of the pathways identified suggest possible avenues for augmentation pharmacotherapy of schizophrenia with other existing agents, such as benzodiazepines, anticonvulsants and lipid modulating agents. Other pathways are new potential targets for drug development. Lastly, a comparison with our earlier work on bipolar disorder illuminates the significant molecular overlap between schizophrenia and bipolar disorder.
Collapse
Affiliation(s)
- H Le-Niculescu
- Laboratory of Neurophenomics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Teutsch C, Kondo RP, Dederko DA, Chrast J, Chien KR, Giles WR. Spatial distributions of Kv4 channels and KChip2 isoforms in the murine heart based on laser capture microdissection. Cardiovasc Res 2006; 73:739-49. [PMID: 17289005 DOI: 10.1016/j.cardiores.2006.11.034] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2006] [Revised: 11/06/2006] [Accepted: 11/27/2006] [Indexed: 10/23/2022] Open
Abstract
OBJECTIVE Regional differences in repolarizing K(+) current densities and expression levels of their molecular components are important for coordinating the pattern of electrical excitation and repolarization of the heart. The small size of hearts from mice may obscure these interventricular and/or transmural expression differences of K(+) channels. We have examined this possibility in adult mouse ventricle using a technology that provides very high spatial resolution of tissue collection. METHODS Conventional manual dissection and laser capture microdissection (LCM) were utilized to dissect tissue from distinct ventricular regions. RNA was isolated from epicardial, mid-myocardial and endocardial layers of both the right and left ventricles. Real-time RT-PCR was used to quantify the transcript expression in these different regions. RESULTS LCM revealed significant interventricular and transmural gradients for both Kv4.2 and the alpha-subunit of KChIP2. The expression profile of a second K(+) channel transcript, Kir2.1, which is responsible for the inwardly rectifying K(+) current I(k1), showed no interventricular or transmural gradients and therefore served as a negative control. CONCLUSIONS Our findings are in contrast to previous reports of a relatively uniform left ventricular transmural pattern of expression of Kv4.2, Kv4.3 and KChIP2 in adult mouse heart, which appear to be different than that in larger mammals. Specifically, our results demonstrate significant epi- to endocardial differences in the patterns of expression of both Kv4.2 and KChIP2.
Collapse
Affiliation(s)
- Christine Teutsch
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | | | | | | | | | | |
Collapse
|