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Di Re J, Marini M, Hussain SI, Singh AK, Venkatesh A, Alshammari MA, Alshammari TK, Hamoud ARA, Imami AS, Haghighijoo Z, Fularcyzk N, Stertz L, Hawes D, Mosebarger A, Jernigan J, Chaljub C, Nehme R, Walss-Bass C, Schulmann A, Vawter MP, McCullumsmith R, Damoiseaux RD, Limon A, Labate D, Wells MF, Laezza F. βIV spectrin abundancy, cellular distribution and sensitivity to AKT/GSK3 regulation in schizophrenia. Mol Psychiatry 2025:10.1038/s41380-025-02917-1. [PMID: 39920295 DOI: 10.1038/s41380-025-02917-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/06/2024] [Accepted: 01/30/2025] [Indexed: 02/09/2025]
Abstract
Schizophrenia (SCZ) is a complex psychiatric disorder with unclear biological mechanisms. Spectrins, cytoskeletal proteins linked to neurodevelopmental disorders, are regulated by the AKT/GSK3 pathway, which is implicated in SCZ. However, the impact of SCZ-related dysregulation of this pathway on spectrin expression and distribution remains unexplored. Here, we show that βIV spectrin protein levels were reduced in neurons of the dorsolateral prefrontal cortex in SCZ postmortem samples compared to healthy control (HC) from the Human Brain Collection Core (HBCC). To investigate potential links between βIV spectrin and the AKT/GSK3 pathway, we analyzed the PsychEncode dataset, revealing elevated SPTBN4 and AKT2 mRNA levels with correlated gene transcription in both HCs and individuals with SCZ. Next, computational tools were employed to identify potential AKT and GSK3 phosphorylation sites on βIV spectrin, and two GSK3 sites were validated through in vitro assays. To assess whether βIV spectrin distribution and sensitivity to AKT/GSK3 are altered in SCZ, we used iPSC-derived neurons from two independent cohorts of patients with significantly increased familial genetic risk for the disorder. Alteration in βIV spectrin levels and sensitivity to AKT/GSK3 inhibitors were consistently observed across both cohorts. Importantly, a Random Forest classifier applied to βIV spectrin imaging achieved up to 98% accuracy in classifying cells by diagnosis in postmortem samples, and by diagnosis or diagnosis × perturbation in iPSC samples. These findings reveal altered βIV spectrin levels and AKT/GSK3 sensitivity in SCZ, identifying βIV spectrin image-based endophenotypes as robust, generalizable predictive biomarkers of SCZ, with the potential for scalable clinical applications.
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Affiliation(s)
- Jessica Di Re
- Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Michela Marini
- Department of Mathematics, University of Houston, Houston, TX, USA
| | | | - Aditya K Singh
- Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Akshaya Venkatesh
- MD-PhD Combined Program, University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Musaad A Alshammari
- Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Tahani K Alshammari
- Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Abdul-Rizaq Ali Hamoud
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Ali Sajid Imami
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Zahra Haghighijoo
- Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | | | - Laura Stertz
- Louis A. Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Derek Hawes
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Angela Mosebarger
- Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Jordan Jernigan
- Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Claire Chaljub
- Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Ralda Nehme
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Consuelo Walss-Bass
- Louis A. Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Anton Schulmann
- Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, USA
| | - Marquis P Vawter
- Functional Genomics Laboratory, Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA, USA
| | - Robert McCullumsmith
- Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
- Neurosciences Institute, Promedica, Toledo, OH, USA
| | - Robert D Damoiseaux
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
- Department of Bioengineering, University of California, Los Angeles, CA, USA
- California NanoSystems Institute, University of California, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA
| | - Agenor Limon
- Department of Neurology, University of Texas Medical Branch at Galveston, Galveston, TX, USA
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Demetrio Labate
- Department of Mathematics, University of Houston, Houston, TX, USA
| | - Michael F Wells
- Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA
| | - Fernanda Laezza
- Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
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Kalejahi P, Kheirouri S, Noorazar SG. A randomized controlled trial of Vitamin D supplementation in Iranian patients with schizophrenia: Effects on serum levels of glycogen synthase kinase-3β and symptom severity. Int J Psychiatry Med 2023; 58:559-575. [PMID: 37545122 DOI: 10.1177/00912174231193303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
BACKGROUND Growing evidence has shown that hypovitaminosis D is a risk factor for developing schizophrenia and comorbid conditions. Therefore, this study aimed to examine the effect of vitamin D supplementation on serum levels of vitamin D, metabolic factors related to insulin resistance (IR) and the severity of the disorder in patients with schizophrenia. METHODS Forty-eight chronic male patients with schizophrenia with vitamin D deficiency (≤20 ng/mL= (≤50 nmol/l) were selected and randomly assigned to vitamin D treatment and placebo groups. Subjects were supplemented for 8 weeks with vitamin D (2000 IU/day) or placebo. RESULTS Within-group comparison revealed that the vitamin D group had a significant reduction in waist circumference, Positive and Negative Syndrome Scale - total score (PANSS-TS), and glycogen synthase kinase 3 beta (GSK-3β) levels (P = .022, P = <.001 and P = .013, respectively). On the other hand, the placebo group showed a significant increase in the level of fasting serum insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (P = .003 and P = .003). The between-group comparison showed a significant difference in terms of PANSS-TS, GSK-3β, fasting serum insulin (FSI), and HOMA-IR (P = .022, P = .048, P = .013 and P = .014 respectively). CONCLUSIONS Among vitamin D deficient patients with schizophrenia, vitamin D supplementation may affect GSK-3 β, an important biomarker in schizophrenia and insulin resistance. In addition, vitamin D supplementation in such patients may reduce the disorder's symptom severity.
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Affiliation(s)
- Parinaz Kalejahi
- Department of Nutrition, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sorayya Kheirouri
- Department of Nutrition, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Gholamreza Noorazar
- Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Hu L, Zhang L. Adult neural stem cells and schizophrenia. World J Stem Cells 2022; 14:219-230. [PMID: 35432739 PMCID: PMC8968214 DOI: 10.4252/wjsc.v14.i3.219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/18/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits. Although many genetic risk factors have been identified, SCZ is also considered as a neurodevelopmental disorder. Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes. Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood. These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination, which have been shown to be closely linked with many psychiatric disorders, such as SCZ. Here in this review, we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors. We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets, which could facilitate the development of novel medication and treatment.
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Affiliation(s)
- Ling Hu
- Department of Laboratory Animal Science and Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center) and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
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Candidate metabolic biomarkers for schizophrenia in CNS and periphery: Do any possible associations exist? Schizophr Res 2020; 226:95-110. [PMID: 30935700 DOI: 10.1016/j.schres.2019.03.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 03/08/2019] [Accepted: 03/11/2019] [Indexed: 02/07/2023]
Abstract
Due to the limitations of analytical techniques and the complicity of schizophrenia, nowadays it is still a challenge to diagnose and stratify schizophrenia patients accurately. Many attempts have been made to identify and validate available biomarkers for schizophrenia from CSF and/or peripheral blood in clinical studies with consideration to disease stages, antipsychotic effects and even gender differences. However, conflicting results handicap the validation and application of biomarkers for schizophrenia. In view of availability and feasibility, peripheral biomarkers have superior advantages over biomarkers in CNS. Meanwhile, schizophrenia is considered to be a devastating neuropsychiatric disease mainly taking place in CNS featured by widespread defects in multiple metabolic pathways whose dynamic interactions, until recently, have been difficult to difficult to investigate. Evidence for these alterations has been collected piecemeal, limiting the potential to inform our understanding of the interactions among relevant biochemical pathways. Taken these points together, it will be interesting to investigate possible associations of biomarkers between CNS and periphery. Numerous studies have suggested putative correlations within peripheral and CNS systems especially for dopaminergic and glutamatergic metabolic biomarkers. In addition, it has been demonstrated that blood concentrations of BDNF protein can also reflect its changes in the nervous system. In turn, BDNF also interacts with glutamatergic, dopaminergic and serotonergic systems. Therefore, this review will summarize metabolic biomarkers identified both in the CNS (brain tissues and CSF) and peripheral blood. Further, more attentions will be paid to discussing possible physical and functional associations between CNS and periphery, especially with respect to BDNF.
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Weng YT, Chien T, Kuan II, Chern Y. The TRAX, DISC1, and GSK3 complex in mental disorders and therapeutic interventions. J Biomed Sci 2018; 25:71. [PMID: 30285728 PMCID: PMC6171312 DOI: 10.1186/s12929-018-0473-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 09/25/2018] [Indexed: 01/15/2023] Open
Abstract
Psychiatric disorders (such as bipolar disorder, depression, and schizophrenia) affect the lives of millions of individuals worldwide. Despite the tremendous efforts devoted to various types of psychiatric studies and rapidly accumulating genetic information, the molecular mechanisms underlying psychiatric disorder development remain elusive. Among the genes that have been implicated in schizophrenia and other mental disorders, disrupted in schizophrenia 1 (DISC1) and glycogen synthase kinase 3 (GSK3) have been intensively investigated. DISC1 binds directly to GSK3 and modulates many cellular functions by negatively inhibiting GSK3 activity. The human DISC1 gene is located on chromosome 1 and is highly associated with schizophrenia and other mental disorders. A recent study demonstrated that a neighboring gene of DISC1, translin-associated factor X (TRAX), binds to the DISC1/GSK3β complex and at least partly mediates the actions of the DISC1/GSK3β complex. Previous studies also demonstrate that TRAX and most of its interacting proteins that have been identified so far are risk genes and/or markers of mental disorders. In the present review, we will focus on the emerging roles of TRAX and its interacting proteins (including DISC1 and GSK3β) in psychiatric disorders and the potential implications for developing therapeutic interventions.
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Affiliation(s)
- Yu-Ting Weng
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, Taipei, 115, Taiwan, Republic of China.,Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan, Republic of China
| | - Ting Chien
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, Taipei, 115, Taiwan, Republic of China
| | - I-I Kuan
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, Taipei, 115, Taiwan, Republic of China
| | - Yijuang Chern
- Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, Taipei, 115, Taiwan, Republic of China. .,Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan, Republic of China.
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Duda P, Wiśniewski J, Wójtowicz T, Wójcicka O, Jaśkiewicz M, Drulis-Fajdasz D, Rakus D, McCubrey JA, Gizak A. Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging. Expert Opin Ther Targets 2018; 22:833-848. [PMID: 30244615 DOI: 10.1080/14728222.2018.1526925] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Glycogen synthase kinase 3 (GSK3) is at the center of cellular signaling and controls various aspects of brain functions, including development of the nervous system, neuronal plasticity and onset of neurodegenerative disorders. Areas covered: In this review, recent efforts in elucidating the roles of GSK3 in neuronal plasticity and development of brain pathologies; Alzheimer's and Parkinson's disease, schizophrenia, and age-related neurodegeneration are described. The effect of microglia and astrocytes on development of the pathological states is also discussed. Expert opinion: GSK3β and its signaling pathway partners hold great promise as therapeutic target(s) for a multitude of neurological disorders. Activity of the kinase is often elevated in brain disorders. However, due to the wide range of GSK3 cellular targets, global inhibition of the kinase leads to severe side-effects and GSK3 inhibitors rarely reach Phase-2 clinical trials. Thus, a selective modulation of a specific cellular pool of GSK3 or specific down- or upstream partners of the kinase might provide more efficient anti-neurodegenerative therapies.
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Affiliation(s)
- Przemysław Duda
- a Department of Molecular Physiology and Neurobiology , University of Wroclaw , Wroclaw , Poland
| | - Janusz Wiśniewski
- a Department of Molecular Physiology and Neurobiology , University of Wroclaw , Wroclaw , Poland
| | - Tomasz Wójtowicz
- a Department of Molecular Physiology and Neurobiology , University of Wroclaw , Wroclaw , Poland
| | - Olga Wójcicka
- a Department of Molecular Physiology and Neurobiology , University of Wroclaw , Wroclaw , Poland
| | - Michał Jaśkiewicz
- a Department of Molecular Physiology and Neurobiology , University of Wroclaw , Wroclaw , Poland
| | - Dominika Drulis-Fajdasz
- a Department of Molecular Physiology and Neurobiology , University of Wroclaw , Wroclaw , Poland
| | - Dariusz Rakus
- a Department of Molecular Physiology and Neurobiology , University of Wroclaw , Wroclaw , Poland
| | - James A McCubrey
- b Department of Microbiology and Immunology , Brody School of Medicine at East Carolina University , Greenville , NC , USA
| | - Agnieszka Gizak
- a Department of Molecular Physiology and Neurobiology , University of Wroclaw , Wroclaw , Poland
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Mohammadi A, Rashidi E, Amooeian VG. Brain, blood, cerebrospinal fluid, and serum biomarkers in schizophrenia. Psychiatry Res 2018; 265:25-38. [PMID: 29680514 DOI: 10.1016/j.psychres.2018.04.036] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 03/20/2018] [Accepted: 04/11/2018] [Indexed: 12/29/2022]
Abstract
Over the last decade, finding a reliable biomarker for the early detection of schizophrenia (Scz) has been a topic of interest. The main goal of the current review is to provide a comprehensive view of the brain, blood, cerebrospinal fluid (CSF), and serum biomarkers of Scz disease. Imaging studies have demonstrated that the volumes of the corpus callosum, thalamus, hippocampal formation, subiculum, parahippocampal gyrus, superior temporal gyrus, prefrontal and orbitofrontal cortices, and amygdala-hippocampal complex were reduced in patients diagnosed with Scz. It has been revealed that the levels of interleukin 1β (IL-1β), IL-6, IL-8, and TNF-α were increased in patients with Scz. Decreased mRNA levels of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), neurotrophin-3 (NT-3), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) genes have also been reported in Scz patients. Genes with known strong relationships with this disease include BDNF, catechol-O-methyltransferase (COMT), regulator of G-protein signaling 4 (RGS4), dystrobrevin-binding protein 1 (DTNBP1), neuregulin 1 (NRG1), Reelin (RELN), Selenium-binding protein 1 (SELENBP1), glutamic acid decarboxylase 67 (GAD 67), and disrupted in schizophrenia 1 (DISC1). The levels of dopamine, tyrosine hydroxylase (TH), serotonin or 5-hydroxytryptamine (5-HT) receptor 1A and B (5-HTR1A and 5-HTR1B), and 5-HT1B were significantly increased in Scz patients, while the levels of gamma-aminobutyric acid (GABA), 5-HT transporter (5-HTT), and 5-HT receptor 2A (5-HTR2A) were decreased. The increased levels of SELENBP1 and Glycogen synthase kinase 3 subunit α (GSK3α) genes in contrast with reduced levels of B-cell translocation gene 1 (BTG1), human leukocyte antigen DRB1 (HLA-DRB1), heterogeneous nuclear ribonucleoprotein A3 (HNRPA3), and serine/arginine-rich splicing factor 1 (SFRS1) genes have also been reported. This review covers various dysregulation of neurotransmitters and also highlights the strengths and weaknesses of studies attempting to identify candidate biomarkers.
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Affiliation(s)
- Alireza Mohammadi
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Ehsan Rashidi
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Ghasem Amooeian
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
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Increased platelet glycogen sysnthase kinase 3beta in first-episode psychosis. Schizophr Res 2018; 195:402-405. [PMID: 28888361 DOI: 10.1016/j.schres.2017.08.062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 08/31/2017] [Accepted: 08/31/2017] [Indexed: 11/23/2022]
Abstract
Past studies have linked intracellular pathways related to psychotic disorders to the GSK3B enzyme. This study aimed to investigate GSK3B protein expression and phosphorylation in drug-naïve first-episode psychosis patients (n=43) at baseline and following symptom remission, and in healthy controls (n=77). At baseline GSK3B total level was higher in patients (p<0.001). In schizophrenia spectrum patients (n=25) GSK3B total and phosphorylated levels were higher than in controls and patients with other non-affective psychotic disorders (n=18) (p<0.001; p=0.027; p=0.05 respectively). No enzyme changes were found after clinical remission. The implication of this finding for the biology of psychoses warrants further studies to clarify whether increased GSK3B may be useful as a biomarker for psychosis in general, and schizophrenia in particular.
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Paquet C, Dumurgier J, Hugon J. Pro-Apoptotic Kinase Levels in Cerebrospinal Fluid as Potential Future Biomarkers in Alzheimer's Disease. Front Neurol 2015; 6:168. [PMID: 26300842 PMCID: PMC4523792 DOI: 10.3389/fneur.2015.00168] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 07/20/2015] [Indexed: 12/22/2022] Open
Abstract
Alzheimer’s disease (AD) is characterized by the accumulation of Aβ peptides, hyperphosphorylated tau proteins, and neuronal loss in the brain of affected patients. The causes of neurodegeneration in AD are not clear, but apoptosis could be one of the cell death mechanisms. According to the amyloid hypothesis, abnormal aggregation of Aβ leads to altered kinase activities inducing tau phosphorylation and neuronal degeneration. Several studies have shown that pro-apoptotic kinases could be a link between Aβ and tau anomalies. Here, we present recent evidences from AD experimental models and human studies that three pro-apoptotic kinases (double-stranded RNA kinase (PKR), glycogen synthase kinase-3β, and C-Jun terminal kinase (JNK) could be implicated in AD physiopathology. These kinases are detectable in human fluids and the analysis of their levels could be used as potential surrogate markers to evaluate cell death and clinical prognosis. In addition to current biomarkers (Aβ1–42, tau, and phosphorylated tau), these new evaluations could bring about valuable information on potential innovative therapeutic targets to alter the clinical evolution.
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Affiliation(s)
- Claire Paquet
- INSERM UMR-S942, Centre Mémoire de Ressources et de Recherche (CMRR) Paris Nord Ile de France, Groupe Hospitalier Lariboisière Fernand-Widal Saint-Louis, AP-HP, Université Paris Diderot , Paris , France
| | - Julien Dumurgier
- INSERM UMR-S942, Centre Mémoire de Ressources et de Recherche (CMRR) Paris Nord Ile de France, Groupe Hospitalier Lariboisière Fernand-Widal Saint-Louis, AP-HP, Université Paris Diderot , Paris , France
| | - Jacques Hugon
- INSERM UMR-S942, Centre Mémoire de Ressources et de Recherche (CMRR) Paris Nord Ile de France, Groupe Hospitalier Lariboisière Fernand-Widal Saint-Louis, AP-HP, Université Paris Diderot , Paris , France
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Ferreira AS, Raposo NRB, Sallet PC, Van de Bilt MT, Machado-Vieira R, Talib LL, Gattaz WF. Lower phosphorylated glycogen synthase kinase-3B levels in platelets of patients with schizophrenia: increment by olanzapine treatment. Eur Arch Psychiatry Clin Neurosci 2015; 265:167-70. [PMID: 24831601 DOI: 10.1007/s00406-014-0505-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Accepted: 05/01/2014] [Indexed: 11/28/2022]
Abstract
Glycogen synthase kinase-3B (GSK-3B) is involved with important neuronal processes such as cell survival, gene regulation, mood and cognitive performance. This enzyme is inactivated by phosphorylation at the phospho-Ser9 site. We compared GSK-3B levels in patients with schizophrenia to a health control group. The levels of phosphorylated and total GSK-3B in platelets of ten drug-free patients, ten long-term olanzapine treated patients and 20 healthy controls were determined by means of an enzyme immunoassay kit. In drug-free patients, GSK-3B levels were accessed again after 8 weeks on treatment with olanzapine. At baseline, drug-free patients presented lower phosphorylated and total GSK-3B levels than healthy controls (p < 0.05). After 8 weeks on olanzapine treatment, phosphorylated and total GSK-3B levels were significantly increased (p < 0.01). Reduced phospho-Ser9-GSK-3B in schizophrenia may disrupt signal-transduction pathways and influence crucial cellular processes, such as transcription, apoptosis, stress response and cell proliferation. Further studies should clarify whether the increment of GSK-3B phosphorylation by olanzapine is related to its antipsychotic effects.
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Affiliation(s)
- Aline Siqueira Ferreira
- Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Rua Dr Ovídio Pires de Campos, 785, 3rd Floor, São Paulo, 05403-010, Brazil
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O'Leary O, Nolan Y. Glycogen synthase kinase-3 as a therapeutic target for cognitive dysfunction in neuropsychiatric disorders. CNS Drugs 2015; 29:1-15. [PMID: 25380674 DOI: 10.1007/s40263-014-0213-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) is involved in a broad range of cellular processes including cell proliferation, apoptosis and inflammation. It is now also increasingly acknowledged as having a role to play in cognitive-related processes such as neurogenesis, synaptic plasticity and neural cell survival. Cognitive impairment represents a major debilitating feature of many neurodegenerative and psychiatric disorders, including Alzheimer's disease, mood disorders, schizophrenia and fragile X syndrome, as well as being a result of traumatic brain injury or cranial irradiation. Accordingly, GSK-3 has been identified as an important therapeutic target for cognitive impairment, and recent preclinical studies have yielded important evidence demonstrating that GSK-3 inhibitors may be useful therapeutic interventions for restoring cognitive function in some of these brain disorders. The current review summarises the role of GSK-3 as a regulator of cognitive-dependent functions, examines current preclinical and clinical evidence of the potential of GSK-3 inhibitors as therapeutic agents for cognitive impairments in neuropsychiatric disorders, and offers some insight into the current obstacles that are impeding the clinical use of selective GSK-3 inhibitors in the treatment of cognitive impairment.
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Affiliation(s)
- Olivia O'Leary
- Department of Anatomy and Neuroscience, Western Gateway Building, University College Cork, Room 4.10, Cork, Ireland
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Vasic N, Connemann BJ, Wolf RC, Tumani H, Brettschneider J. Cerebrospinal fluid biomarker candidates of schizophrenia: where do we stand? Eur Arch Psychiatry Clin Neurosci 2012; 262:375-91. [PMID: 22173848 DOI: 10.1007/s00406-011-0280-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Accepted: 12/03/2011] [Indexed: 02/07/2023]
Abstract
Here, we review the cerebrospinal fluid (CSF) candidate markers with regard to their clinical relevance as potential surrogates for disease activity, prognosis assessment, and predictors of treatment response. We searched different online databases such as MEDLINE and EMBASE for studies on schizophrenia and CSF. Initial studies on cerebrospinal fluid in patients with schizophrenia revealed increased brain-blood barrier permeability with elevated total protein content, increased CSF-to-serum ratio for albumin, and intrathecal production of immunoglobulins in subgroups of patients. Analyses of metabolites in CSF suggest alterations within glutamatergic neurotransmission as well as monoamine and cannabinoid metabolism. Decreased levels of brain-derived neurotrophic factor and nerve growth factor in CSF of first-episode patients with schizophrenia reported in recent studies point to a dysregulation of neuroprotective and neurodevelopmental processes. Still, these findings must be considered as non-specific. A more profound characterization of the particular psychopathological profiles, the investigation of patients in the prodromal phase or within the first episode of schizophrenia promoting longitudinal investigations, implementation of different approaches of proteomics, and rigorous adherence to standard procedures based on international CSF guidelines are necessary to improve the quality of CSF studies in schizophrenia, paving the way for identification of syndrome-specific biomarker candidates.
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Affiliation(s)
- Nenad Vasic
- Department of Psychiatry and Psychotherapy III, University of Ulm, Germany.
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Manceur AP, Tseng M, Holowacz T, Witterick I, Weksberg R, McCurdy RD, Warsh JJ, Audet J. Inhibition of glycogen synthase kinase-3 enhances the differentiation and reduces the proliferation of adult human olfactory epithelium neural precursors. Exp Cell Res 2011; 317:2086-98. [PMID: 21708147 DOI: 10.1016/j.yexcr.2011.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2010] [Revised: 06/07/2011] [Accepted: 06/10/2011] [Indexed: 01/12/2023]
Abstract
The olfactory epithelium (OE) contains neural precursor cells which can be easily harvested from a minimally invasive nasal biopsy, making them a valuable cell source to study human neural cell lineages in health and disease. Glycogen synthase kinase-3 (GSK-3) has been implicated in the etiology and treatment of neuropsychiatric disorders and also in the regulation of murine neural precursor cell fate in vitro and in vivo. In this study, we examined the impact of decreased GSK-3 activity on the fate of adult human OE neural precursors in vitro. GSK-3 inhibition was achieved using ATP-competitive (6-bromoindirubin-3'-oxime and CHIR99021) or substrate-competitive (TAT-eIF2B) inhibitors to eliminate potential confounding effects on cell fate due to off-target kinase inhibition. GSK-3 inhibitors decreased the number of neural precursor cells in OE cell cultures through a reduction in proliferation. Decreased proliferation was not associated with a reduction in cell survival but was accompanied by a reduction in nestin expression and a substantial increase in the expression of the neuronal differentiation markers MAP1B and neurofilament (NF-M) after 10 days in culture. Taken together, these results suggest that GSK-3 inhibition promotes the early stages of neuronal differentiation in cultures of adult human neural precursors and provide insights into the mechanisms by which alterations in GSK-3 signaling affect adult human neurogenesis, a cellular process strongly suspected to play a role in the etiology of neuropsychiatric disorders.
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Affiliation(s)
- Aziza P Manceur
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
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15
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Xu CM, Wang J, Wu P, Xue YX, Zhu WL, Li QQ, Zhai HF, Shi J, Lu L. Glycogen synthase kinase 3β in the nucleus accumbens core is critical for methamphetamine-induced behavioral sensitization. J Neurochem 2011; 118:126-39. [DOI: 10.1111/j.1471-4159.2011.07281.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Matigian N, Abrahamsen G, Sutharsan R, Cook AL, Vitale AM, Nouwens A, Bellette B, An J, Anderson M, Beckhouse AG, Bennebroek M, Cecil R, Chalk AM, Cochrane J, Fan Y, Féron F, McCurdy R, McGrath JJ, Murrell W, Perry C, Raju J, Ravishankar S, Silburn PA, Sutherland GT, Mahler S, Mellick GD, Wood SA, Sue CM, Wells CA, Mackay-Sim A. Disease-specific, neurosphere-derived cells as models for brain disorders. Dis Model Mech 2010; 3:785-98. [PMID: 20699480 DOI: 10.1242/dmm.005447] [Citation(s) in RCA: 157] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery.
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Affiliation(s)
- Nicholas Matigian
- National Centre for Adult Stem Cell Research, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, QLD 4111, Australia
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Glycogen synthase kinase-3beta in the platelets of patients with mood disorders: effect of treatment. J Psychiatr Res 2010; 44:143-8. [PMID: 19717166 DOI: 10.1016/j.jpsychires.2009.07.009] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2008] [Revised: 07/07/2009] [Accepted: 07/17/2009] [Indexed: 11/24/2022]
Abstract
Glycogen synthase kinase (GSK)-3beta, an important component of the Wnt signaling pathway, is involved in numerous cellular functions. That GSK-3beta may be involved in the pathophysiology of bipolar (BP) illness is based on the observation that lithium, a mood-stabilizing drug, inhibits GSK-3beta both in vitro and in vivo. We determined the protein expression of GSK-3beta in the cytosol and membrane fractions of the platelets obtained from patients with major depressive disorder (MDD) and BP illness, before treatment and after treatment with antidepressants or mood-stabilizing drugs, respectively. Protein expression was determined using the Western blot technique. We observed that the protein expression of GSK-3beta was significantly reduced in the membrane and cytosol fractions of platelets from drug-free patients with BP illness, but not from the drug-free patients with MDD, compared with normal control subjects. Treatment with mood-stabilizing drugs significantly increased the protein expression of GSK-3beta in the membrane and cytosol fractions of platelets from BP patients compared with pre-treatment levels, and the post-treatment levels were similar to those observed in normal control subjects. On the other hand, there was no significant effect of treatment with antidepressants on GSK-3beta protein expression either in the membrane or in the cytosol fractions of platelets from MDD patients. These results suggest that GSK-3beta may play an important role in the pathophysiology of BP illness but not MDD and that its abnormality may be corrected by treatment with mood-stabilizing drugs, suggesting that GSK-3beta may be a state rather than a trait marker for BP illness.
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Girgis RR, Javitch JA, Lieberman JA. Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway. Mol Psychiatry 2008; 13:918-29. [PMID: 18414407 PMCID: PMC3618283 DOI: 10.1038/mp.2008.40] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The exact therapeutic mechanism of action of antipsychotic drugs remains unclear. Recent evidence has shown that second-generation antipsychotic drugs (SGAs) are differentially associated with metabolic side effects compared to first-generation antipsychotic drugs (FGAs). Their proclivity to cause metabolic disturbances correlates, to some degree, with their comparative efficacy. This is particularly the case for clozapine and olanzapine. In addition, the insulin signaling pathway is vital for normal brain development and function. Abnormalities of this pathway have been found in persons with schizophrenia and antipsychotic drugs may ameliorate some of these alterations. This prompted us to hypothesize that the therapeutic antipsychotic and adverse metabolic effects of antipsychotic drugs might be related to a common pharmacologic mechanism. This article reviews insulin metabolism in the brain and related abnormalities associated with schizophrenia with the goals of gaining insight into antipsychotic drug effects and possibly also into the pathophysiology of schizophrenia. Finally, we speculate about one potential mechanism of action (that is, functional selectivity) that would be consistent with the data reviewed herein and make suggestions for the future investigation that is required before a therapeutic agent based on these data can be realized.
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Affiliation(s)
- RR Girgis
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA,New York State Psychiatric Institute, New York, NY, USA
| | - JA Javitch
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA,New York State Psychiatric Institute, New York, NY, USA
| | - JA Lieberman
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA,New York State Psychiatric Institute, New York, NY, USA
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Abstract
Our current understanding of the Wnt-dependent signaling pathways is mainly based on studies performed in a number of model organisms including, Xenopus, Drosophila melanogaster, Caenorhabditis elegans and mammals. These studies clearly indicate that the Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Wnt pathways have been shown to regulate cell proliferation, morphology, motility as well as cell fate. The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several pathological disorders including cancer, retinopathy, tetra-amelia and bone and cartilage disease such as arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer’s disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research. In this review, we wish to present a focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development. We also want to provide information on a selection of potential drug targets within these pathways for oncology drug discovery, and summarize current data on approaches, including the development of small-molecule inhibitors, that have shown relevant effects on the Wnt-dependent signaling pathways.
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Affiliation(s)
- Nico Janssens
- Department of Biochemistry, University of Antwerp, Wilrijk, Belgium
| | - Michel Janicot
- Johnson & Johnson Pharmaceutical R & D, Oncology Discovery Research & Early Development, Beerse, Belgium
| | - Tim Perera
- Johnson & Johnson Pharmaceutical R & D, Oncology Discovery Research & Early Development, Beerse, Belgium
- Johnson & Johnson Pharmaceutical R & D, Oncology Discovery Research & Early Development, Turnhoutseweg 30, B-2340 Beerse, Belgium
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Lovestone S, Killick R, Di Forti M, Murray R. Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci 2007; 30:142-9. [PMID: 17324475 DOI: 10.1016/j.tins.2007.02.002] [Citation(s) in RCA: 158] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2006] [Revised: 01/26/2007] [Accepted: 02/14/2007] [Indexed: 12/20/2022]
Abstract
Converging evidence suggests that the regulation of glycogen synthase kinase 3 (GSK-3) might be important in schizophrenia. Atypical and typical antipsychotic drugs alter GSK-3 activity, as do drugs that induce psychosis. GSK-3 regulatory pathways are altered in schizophrenia, and many of the genes associated with schizophrenia directly or indirectly regulate GSK-3 activity. We propose a variant on the neurodevelopment and dopamine hypotheses of schizophrenia, whereby (i) an early dysfunction in GSK-3 regulation has neurodevelopmental consequences that predispose to disease and (ii) dysfunction in GSK-3 regulation in the adult brain alters dopamine signalling events, causing psychotic symptoms and cognitive dysfunction. If, as we suggest, GSK-3 regulation is crucial to schizophrenia, the Wnt and insulin signalling pathways become targets for therapy.
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Affiliation(s)
- Simon Lovestone
- Departments of Psychological Medicine and Neuroscience Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK.
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Levine J, Sela BA, Osher Y, Belmaker RH. High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:1181-91. [PMID: 16115716 DOI: 10.1016/j.pnpbp.2005.06.029] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/17/2005] [Indexed: 10/25/2022]
Abstract
Elevated plasma homocysteine has been found to be a risk factor for Alzheimer's disease as well as cerebral vascular disease, suggesting that some risk factors can accelerate or increase the severity of several CNS disease processes. We screened plasma total homocysteine levels of 193 schizophrenic patients vs. 762 controls for plasma homocysteine levels. The effect of schizophrenia was marked (p<0.0001) and mean homocysteine level was 16.3+/-12 (S.D.) microM in schizophrenic patients vs. 10.6+/-3.6 (S.D.) microM in healthy controls. The increase was almost entirely in young male schizophrenic patients. It seemed important to determine if this finding is already present in newly admitted schizophrenic patients. Serum homocysteine levels were studied in 184 consecutively admitted schizophrenic patients and 305 control subjects. Homocysteine levels were markedly increased in this population of newly admitted schizophrenic patients, especially in young males. However, no difference was found for CSF homocysteine levels between schizophrenia patients and controls. We also examined homocysteine levels in 41 euthymic outpatients with bipolar disorder. Functional deterioration in patients was rated as 'present' or 'absent' by consensus of two treating clinicians. Young male bipolar patients were found to have higher homocysteine levels than controls. Among the male subjects, bipolar patients showing deterioration had homocysteine levels which were significantly higher than other patients. We attempted to develop a model of homocysteine neurotoxicity in mice. Mice were fed homocysteine in water at a dose of 200 mg/kg per mouse per day. Independent samples of animals were studied at 2 to 6 months with behavioral tests including apomorphine-induced stereotypy and spatial learning and memory in the Morris Water Maze. Homocysteine levels were elevated up to 800% at months 5 and 6 by this procedure. No homocysteine-induced defects were found in any behavioral test until month 5 when mild but statistically significant abnormalities in the Morris Water Maze were detected.
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