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Su Z, Zhang H, Wang Y, Chen B, Zhang Z, Wang B, Liu J, Shi Y, Zhao X. Neural oscillation in bipolar disorder: a systematic review of resting-state electroencephalography studies. Front Neurosci 2024; 18:1424666. [PMID: 39238928 PMCID: PMC11375681 DOI: 10.3389/fnins.2024.1424666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 07/30/2024] [Indexed: 09/07/2024] Open
Abstract
Bipolar disorder (BD) is a severe psychiatric disease with high rates of misdiagnosis and underdiagnosis, resulting in a significant disease burden on both individuals and society. Abnormal neural oscillations have garnered significant attention as potential neurobiological markers of BD. However, untangling the mechanisms that subserve these baseline alternations requires measurement of their electrophysiological underpinnings. This systematic review investigates consistent abnormal resting-state EEG power of BD and conducted an initial exploration into how methodological approaches might impact the study outcomes. This review was conducted in Pubmed-Medline and Web-of-Science in March 2024 to summarize the oscillation changes in resting-state EEG (rsEEG) of BD. We focusing on rsEEG to report spectral power in different frequency bands. We identified 10 studies, in which neural oscillations was compared with healthy individuals (HCs). We found that BD patients had abnormal oscillations in delta, theta, beta, and gamma bands, predominantly characterized by increased power, indicating potential widespread neural dysfunction, involving multiple neural networks and cognitive processes. However, the outcomes regarding alpha oscillation in BD were more heterogeneous, which is thought to be potentially influenced by the disease severity and the diversity of samples. Furthermore, we conducted an initial exploration into how demographic and methodological elements might impact the study outcomes, underlining the importance of implementing standardized data collection methods. Key aspects we took into account included gender, age, medication usage, medical history, the method of frequency band segmentation, and situation of eye open/eye close during the recordings. Therefore, in the face of abnormal multiple oscillations in BD, we need to adopt a comprehensive research approach, consider the multidimensional attributes of the disease and the heterogeneity of samples, and pay attention to the standardized experimental design to improve the reliability and reproducibility of the research results.
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Affiliation(s)
- Ziyao Su
- National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- The second Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Haoran Zhang
- National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Yingtan Wang
- National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Bingxu Chen
- Faculty of Information Technology, Beijing University of Technology, Beijing, China
| | - Zhizhen Zhang
- School of Mathematical Sciences, East China Normal University, Shanghai, China
| | - Bin Wang
- National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Jun Liu
- National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Yuwei Shi
- The second Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xixi Zhao
- National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
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Wang J, Liu Y, Gao Y, Liang J, Wang B, Xia Q, Xie Y, Shan F, Xia Q. Comprehensive bioinformatics analysis and molecular validation of lncRNAs-mediated ceRNAs network in schizophrenia. Life Sci 2022; 312:121205. [PMID: 36410410 DOI: 10.1016/j.lfs.2022.121205] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 10/31/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022]
Abstract
AIMS The present study aimed to investigate how Schizophrenia (SCZ)-specific long non-coding RNAs (lncRNAs) served as competing endogenous RNAs (ceRNAs) to modulate the biological functions and pathways involved in the pathogenesis of SCZ. MAIN METHODS Microarray dataset (GSE54913) was obtained from Gene Expression Omnibus (GEO) database. Differently expressed (DE) lncRNAs and mRNAs were identified by "limma" package. The binding miRNAs of lncRNAs and target mRNAs of shared miRNAs were predicted by miRcode, miRDB, miRTarbase and targetscan databases. Following the ceRNAs theory, interaction network was established and visualized with the cytoscape. Functional enrichment analysis uncovered the concentrated functions and signaling pathways that may be associated with SCZ progression. Protein-protein interaction (PPI) analysis was utilized to determine hub genes. Quantitative real-time PCR (qRT-PCR) and receiver operating characteristic curve (ROC) were performed to evaluate the expression and diagnostic value of ceRNAs members, respectively. KEY FINDINGS DElncRNAs and DEmRNAs were initially screened from GSE54913 to construct the SCZ-related ceRNAs network with 42 nodes and 53 edges. Functional enrichment analysis revealed that ceRNAs members appeared to be highly correlated with transcription factor activation, cell replication and tumor-related pathways. Once validated, a significant ceRNAs subnetwork was proposed as being implicated in the pathogenesis of SCZ. ROC analysis indicated that SCZ-related ceRNAs members may be sensitive diagnostic biomarkers for SCZ. SIGNIFICANCE The significant SCZ-related ceRNAs subnetworks (lncRNA-C2orf48A/hsa-miR-20b-5p,-17-5p/KIF23, FOXJ2) may represent promising predictive and diagnostic biomarkers and provide novel insights into the mechanism by which lncRNAs act as microRNA sponges and contribute to the pathogenesis of SCZ.
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Affiliation(s)
- Jiequan Wang
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China
| | - Yaru Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui 230022, China
| | - Yejun Gao
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China
| | - Jun Liang
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China
| | - Baoshi Wang
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China
| | - Quan Xia
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui 230022, China
| | - Yawen Xie
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui 230022, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China
| | - Feng Shan
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China
| | - Qingrong Xia
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, China; Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China.
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Lu Z, Wang H, Gu J, Gao F. Association between abnormal brain oscillations and cognitive performance in patients with bipolar disorder; Molecular mechanisms and clinical evidence. Synapse 2022; 76:e22247. [PMID: 35849784 DOI: 10.1002/syn.22247] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 05/23/2022] [Accepted: 06/20/2022] [Indexed: 11/10/2022]
Abstract
Brain oscillations have gained great attention in neuroscience during recent decades as functional building blocks of cognitive-sensory processes. Research has shown that oscillations in "alpha," "beta," "gamma," "delta," and "theta" frequency windows are highly modified in brain pathology, including in patients with cognitive impairment like bipolar disorder (BD). The study of changes in brain oscillations can provide fundamental knowledge for exploring neurophysiological biomarkers in cognitive impairment. The present article reviews findings from the role and molecular basis of abnormal neural oscillation and synchronization in the symptoms of patients with BD. An overview of the results clearly demonstrates that, in cognitive-sensory processes, resting and evoked/event-related electroencephalogram (EEG) spectra in the delta, theta, alpha, beta, and gamma bands are abnormally changed in patients with BD showing psychotic features. Abnormal oscillations have been found to be associated with several neural dysfunctions and abnormalities contributing to BD, including abnormal GABAergic neurotransmission signaling, hippocampal cell discharge, abnormal hippocampal neurogenesis, impaired cadherin and synaptic contact-based cell adhesion processes, extended lateral ventricles, decreased prefrontal cortical gray matter, and decreased hippocampal volume. Mechanistically, impairment in calcium voltage-gated channel subunit alpha1 I, neurotrophic tyrosine receptor kinase proteins, genes involved in brain neurogenesis and synaptogenesis like WNT3 and ACTG2, genes involved in the cell adhesion process like CDH12 and DISC1, and gamma-aminobutyric acid (GABA) signaling have been reported as the main molecular contributors to the abnormalities in resting-state low-frequency oscillations in BD patients. Findings also showed the association of impaired synaptic connections and disrupted membrane potential with abnormal beta/gamma oscillatory activity in patients with BD. Of note, the synaptic GABA neurotransmitter has been found to be a fundamental requirement for the occurrence of long-distance synchronous gamma oscillations necessary for coordinating the activity of neural networks between various brain regions. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Zhou Lu
- Department of Neurosurgery, The Affiliated People's Hospital of NingBo University, NingBo, 315000, China
| | - Huixiao Wang
- Department of Neurosurgery, The Affiliated People's Hospital of NingBo University, NingBo, 315000, China
| | - Jiajie Gu
- Department of Neurosurgery, The Affiliated People's Hospital of NingBo University, NingBo, 315000, China
| | - Feng Gao
- Department of Neurosurgery, The Affiliated People's Hospital of NingBo University, NingBo, 315000, China
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Osacka J, Kiss A, Bacova Z, Tillinger A. Effect of Haloperidol and Olanzapine on Hippocampal Cells’ Proliferation in Animal Model of Schizophrenia. Int J Mol Sci 2022; 23:ijms23147711. [PMID: 35887056 PMCID: PMC9323809 DOI: 10.3390/ijms23147711] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/07/2022] [Accepted: 07/12/2022] [Indexed: 12/07/2022] Open
Abstract
Aberrant neurogenesis in the subventricular zone (SVZ) and hippocampus (HIP) contributes to schizophrenia pathogenesis. Haloperidol (HAL) and olanzapine (OLA), commonly prescribed antipsychotics for schizophrenia treatment, affect neurogenesis too. The effect of HAL and OLA on an mHippoE-2 cell line was studied in vitro where we measured the cell number and projection length. In vivo, we studied the gene expression of DCX, Sox2, BDNF, and NeuN in the SVZ and HIP in an MK-801-induced animal schizophrenia model. Cells were incubated with HAL, OLA, and MK-801 for 24, 48, and 72 h. Animals were injected for 6 days with saline or MK801 (0.5 mg/kg), and from the 7th day with either vehicle HAL (1 mg/kg) or OLA (2 mg/kg), for the next 7 days. In vitro, HAL and OLA dose/time-dependently suppressed cells’ proliferation and shortened their projection length. HAL/OLA co-treatment with MK-801 for 24 h reversed HAL’s/OLA’s inhibitory effect. In vivo, HAL and OLA suppressed DCX and NeuN genes’ expression in the HIP and SVZ. MK-801 decreased DCX and NeuN genes’ expression in the HIP and OLA prevented this effect. The data suggest that subchronic HAL/OLA treatment can inhibit DCX and NeuN expression. In an MK-801 schizophrenia model, OLA reversed the MK-801 inhibitory effect on DCX and NeuN and HAL reversed the effect on DCX expression; however, only in the HIP.
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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: 3] [Impact Index Per Article: 1.0] [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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Notaras M, Lodhi A, Dündar F, Collier P, Sayles NM, Tilgner H, Greening D, Colak D. Schizophrenia is defined by cell-specific neuropathology and multiple neurodevelopmental mechanisms in patient-derived cerebral organoids. Mol Psychiatry 2022; 27:1416-1434. [PMID: 34789849 PMCID: PMC9095467 DOI: 10.1038/s41380-021-01316-6] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/03/2021] [Accepted: 09/22/2021] [Indexed: 01/02/2023]
Abstract
Due to an inability to ethically access developing human brain tissue as well as identify prospective cases, early-arising neurodevelopmental and cell-specific signatures of Schizophrenia (Scz) have remained unknown and thus undefined. To overcome these challenges, we utilized patient-derived induced pluripotent stem cells (iPSCs) to generate 3D cerebral organoids to model neuropathology of Scz during this critical period. We discovered that Scz organoids exhibited ventricular neuropathology resulting in altered progenitor survival and disrupted neurogenesis. This ultimately yielded fewer neurons within developing cortical fields of Scz organoids. Single-cell sequencing revealed that Scz progenitors were specifically depleted of neuronal programming factors leading to a remodeling of cell-lineages, altered differentiation trajectories, and distorted cortical cell-type diversity. While Scz organoids were similar in their macromolecular diversity to organoids generated from healthy controls (Ctrls), four GWAS factors (PTN, COMT, PLCL1, and PODXL) and peptide fragments belonging to the POU-domain transcription factor family (e.g., POU3F2/BRN2) were altered. This revealed that Scz organoids principally differed not in their proteomic diversity, but specifically in their total quantity of disease and neurodevelopmental factors at the molecular level. Single-cell sequencing subsequently identified cell-type specific alterations in neuronal programming factors as well as a developmental switch in neurotrophic growth factor expression, indicating that Scz neuropathology can be encoded on a cell-type-by-cell-type basis. Furthermore, single-cell sequencing also specifically replicated the depletion of BRN2 (POU3F2) and PTN in both Scz progenitors and neurons. Subsequently, in two mechanistic rescue experiments we identified that the transcription factor BRN2 and growth factor PTN operate as mechanistic substrates of neurogenesis and cellular survival, respectively, in Scz organoids. Collectively, our work suggests that multiple mechanisms of Scz exist in patient-derived organoids, and that these disparate mechanisms converge upon primordial brain developmental pathways such as neuronal differentiation, survival, and growth factor support, which may amalgamate to elevate intrinsic risk of Scz.
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Affiliation(s)
- Michael Notaras
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Aiman Lodhi
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Friederike Dündar
- Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Paul Collier
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Nicole M Sayles
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Hagen Tilgner
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - David Greening
- La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
- Baker Institute & Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia
| | - Dilek Colak
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA.
- Gale and Ira Drukier Institute for Children's Health, Weill Cornell Medical College, Cornell University, New York, NY, USA.
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Ansari Z, Pawar S, Seetharaman R. Neuroinflammation and oxidative stress in schizophrenia: are these opportunities for repurposing? Postgrad Med 2022; 134:187-199. [PMID: 34766870 DOI: 10.1080/00325481.2021.2006514] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 11/11/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE To summarize the main findings on the subject of neuroinflammation and oxidative stress in patients with Schizophrenia (SCZ). METHODS A narrative review of all the relevant papers known to the authors was conducted. RESULTS SCZ is a chronic, debilitating, neuropsychiatric disorder associated with an immense and adverse impact on both the patient and the caregiver, and impairs the overall quality of life. The current modality of treatment involves the use of antipsychotics to balance the disturbances in the neurotransmitters in the dopaminergic and serotonin pathways in the brain, which have a role to play in SCZ. Contemporary management of SCZ focuses mainly on symptomatic control due to the lack of effective curative treatments.Despite the optimum use of antipsychotics, there is a considerable proportion of the patient population who are poor responders. This has necessitated the exploration of new etiopathologies in order to evolve new modalities of treatment. This narrative review, conducted over a period of 3 months, throws light on the large-scale evidence pointing toward neuroinflammation and oxidative stress as key etiopathological markers that merit further consideration in SCZ, and may even be the basis for devising novel pharmacotherapies for SCZ. CONCLUSIONS This review discusses the various plausible hypotheses, viz., cytokine hypothesis of peripheral inflammation, acute-phase reactants in SCZ, microglial hypothesis of central inflammation, neurogenesis in relation to neuroinflammation, and oxidative stress in SCZ. It also highlights the many opportunities available for repurposing already marketed drugs with anti-inflammatory and antioxidant properties with a view to devising more effective and comprehensive therapies to manage SCZ.
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Affiliation(s)
- Zarrin Ansari
- Department of Pharmacology, Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, India
| | - Sudhir Pawar
- Department of Pharmacology, Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, India
| | - Rajmohan Seetharaman
- Department of Pharmacology, Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, India
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Abrous DN, Koehl M, Lemoine M. A Baldwin interpretation of adult hippocampal neurogenesis: from functional relevance to physiopathology. Mol Psychiatry 2022; 27:383-402. [PMID: 34103674 PMCID: PMC8960398 DOI: 10.1038/s41380-021-01172-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 05/03/2021] [Accepted: 05/12/2021] [Indexed: 02/05/2023]
Abstract
Hippocampal adult neurogenesis has been associated to many cognitive, emotional, and behavioral functions and dysfunctions, and its status as a selected effect or an "appendix of the brain" has been debated. In this review, we propose to understand hippocampal neurogenesis as the process underlying the "Baldwin effect", a particular situation in evolution where fitness does not rely on the natural selection of genetic traits, but on "ontogenetic adaptation" to a changing environment. This supports the view that a strong distinction between developmental and adult hippocampal neurogenesis is made. We propose that their functions are the constitution and the lifelong adaptation, respectively, of a basic repertoire of cognitive and emotional behaviors. This lifelong adaptation occurs through new forms of binding, i.e., association or dissociation of more basic elements. This distinction further suggests that a difference is made between developmental vulnerability (or resilience), stemming from dysfunctional (or highly functional) developmental hippocampal neurogenesis, and adult vulnerability (or resilience), stemming from dysfunctional (or highly functional) adult hippocampal neurogenesis. According to this hypothesis, developmental and adult vulnerability are distinct risk factors for various mental disorders in adults. This framework suggests new avenues for research on hippocampal neurogenesis and its implication in mental disorders.
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Affiliation(s)
- Djoher Nora Abrous
- Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, Neurogenesis and Pathophysiology group, F-33000, Bordeaux, France.
| | - Muriel Koehl
- grid.412041.20000 0001 2106 639XUniv. Bordeaux, INSERM, Neurocentre Magendie, U1215, Neurogenesis and Pathophysiology group, F-33000 Bordeaux, France
| | - Maël Lemoine
- grid.412041.20000 0001 2106 639XUniversity Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France
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Moon SY, Kim M, Lho SK, Oh S, Kim SH, Kwon JS. Systematic Review of the Neural Effect of Electroconvulsive Therapy in Patients with Schizophrenia: Hippocampus and Insula as the Key Regions of Modulation. Psychiatry Investig 2021; 18:486-499. [PMID: 34218638 PMCID: PMC8256139 DOI: 10.30773/pi.2020.0438] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/03/2021] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE Electroconvulsive therapy (ECT) has been the most potent treatment option for treatment-resistant schizophrenia (TRS). However, the underlying neural mechanisms of ECT in schizophrenia remain largely unclear. This paper examines studies that investigated structural and functional changes after ECT in patients with schizophrenia. METHODS We carried out a systematic review with following terms: 'ECT', 'schizophrenia', and the terms of various neuroimaging modalities. RESULTS Among the 325 records available from the initial search in May 2020, 17 studies were included. Cerebral blood flow in the frontal, temporal, and striatal structures was shown to be modulated (n=3), although the results were divergent. Magnetic resonance spectroscopy (MRS) studies suggested that the ratio of N-acetyl-aspartate/creatinine was increased in the left prefrontal cortex (PFC; n=2) and left thalamus (n=1). The hippocampus and insula (n=6, respectively) were the most common regions of structural/functional modulation, which also showed symptom associations. Functional connectivity of the default mode network (DMN; n=5), PFC (n=4), and thalamostriatal system (n=2) were also commonly modulated. CONCLUSION Despite proven effectiveness, there has been a dearth of studies investigating the neurobiological mechanisms underlying ECT. There is preliminary evidence of structural and functional modulation of the hippocampus and insula, functional changes in the DMN, PFC, and thalamostriatal system after ECT in patients with schizophrenia. We discuss the rationale and implications of these findings and the potential mechanism of action of ECT. More studies evaluating the mechanisms of ECT are needed, which could provide a unique window into what leads to treatment response in the otherwise refractory TRS population.
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Affiliation(s)
- Sun-Young Moon
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea
| | - Minah Kim
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea
| | - Silvia Kyungjin Lho
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sanghoon Oh
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea
| | - Se Hyun Kim
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jun Soo Kwon
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, Seoul, Republic of Korea.,Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea
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Langova V, Vales K, Horka P, Horacek J. The Role of Zebrafish and Laboratory Rodents in Schizophrenia Research. Front Psychiatry 2020; 11:703. [PMID: 33101067 PMCID: PMC7500259 DOI: 10.3389/fpsyt.2020.00703] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Accepted: 07/03/2020] [Indexed: 12/11/2022] Open
Abstract
Schizophrenia is a severe disorder characterized by positive, negative and cognitive symptoms, which are still not fully understood. The development of efficient antipsychotics requires animal models of a strong validity, therefore the aims of the article were to summarize the construct, face and predictive validity of schizophrenia models based on rodents and zebrafish, to compare the advantages and disadvantages of these models, and to propose future directions in schizophrenia modeling and indicate when it is reasonable to combine these models. The advantages of rodent models stem primarily from the high homology between rodent and human physiology, neurochemistry, brain morphology and circuitry. The advantages of zebrafish models stem in the high fecundity, fast development and transparency of the embryo. Disadvantages of both models originate in behavioral repertoires not allowing specific symptoms to be modeled, even when the models are combined. Especially modeling the verbal component of certain positive, negative and cognitive symptoms is currently impossible.
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Affiliation(s)
- Veronika Langova
- Translational Neuroscience, National Institute of Mental Health, Prague, Czechia
- Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Karel Vales
- Translational Neuroscience, National Institute of Mental Health, Prague, Czechia
| | - Petra Horka
- Institute for Environmental Studies, Faculty of Science, Charles University, Prague, Czechia
| | - Jiri Horacek
- Third Faculty of Medicine, Charles University, Prague, Czechia
- Brain Electrophysiology, National Institute of Mental Health, Prague, Czechia
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11
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Lopes PC, König B. Wild mice with different social network sizes vary in brain gene expression. BMC Genomics 2020; 21:506. [PMID: 32698762 PMCID: PMC7374831 DOI: 10.1186/s12864-020-06911-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 07/13/2020] [Indexed: 12/14/2022] Open
Abstract
Background Appropriate social interactions influence animal fitness by impacting several processes, such as mating, territory defense, and offspring care. Many studies shedding light on the neurobiological underpinnings of social behavior have focused on nonapeptides (vasopressin, oxytocin, and homologues) and on sexual or parent-offspring interactions. Furthermore, animals have been studied under artificial laboratory conditions, where the consequences of behavioral responses may not be as critical as when expressed under natural environments, therefore obscuring certain physiological responses. We used automated recording of social interactions of wild house mice outside of the breeding season to detect individuals at both tails of a distribution of egocentric network sizes (characterized by number of different partners encountered per day). We then used RNA-seq to perform an unbiased assessment of neural differences in gene expression in the prefrontal cortex, the hippocampus and the hypothalamus between these mice with naturally occurring extreme differences in social network size. Results We found that the neurogenomic pathways associated with having extreme social network sizes differed between the sexes. In females, hundreds of genes were differentially expressed between animals with small and large social network sizes, whereas in males very few were. In males, X-chromosome inactivation pathways in the prefrontal cortex were the ones that better differentiated animals with small from those with large social network sizes animals. In females, animals with small network size showed up-regulation of dopaminergic production and transport pathways in the hypothalamus. Additionally, in females, extracellular matrix deposition on hippocampal neurons was higher in individuals with small relative to large social network size. Conclusions Studying neural substrates of natural variation in social behavior in traditional model organisms in their habitat can open new targets of research for understanding variation in social behavior in other taxa.
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Affiliation(s)
- Patricia C Lopes
- Schmid College of Science and Technology, Chapman University, Orange, CA, USA.
| | - Barbara König
- Department of Evolutionary Biology and Environmental Studies, University of Zurich, Zürich, Switzerland
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12
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Yi Y, Song Y, Lu Y. Parvalbumin Interneuron Activation-Dependent Adult Hippocampal Neurogenesis Is Required for Treadmill Running to Reverse Schizophrenia-Like Phenotypes. Front Cell Dev Biol 2020; 8:24. [PMID: 32117963 PMCID: PMC7010605 DOI: 10.3389/fcell.2020.00024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 01/13/2020] [Indexed: 12/15/2022] Open
Abstract
Physical exercise can alleviate some of the schizophrenia symptoms in patients, the mechanisms, however, are still unclear. To investigate whether the GABAergic interneuron involved in the therapeutic effect of treadmill running on schizophrenia, the parvalbumin (PV)-positive GABAergic interneurons in the dentate gyrus (DG) was specifically activated or abolished and the effects were evaluated. In the MK801-induced schizophrenia-like animal model, we found:(1) Treadmill running rescued the schizophrenia-related behavioral phenotypes, promoted the adult hippocampal neurogenesis, and increased the dendrite number and complexity of newborn neurons. (2) Treadmill running increased the number of PV-positive interneurons in the DG; genetic ablation of these interneurons reduced adult neurogenesis and abolished the effect of treadmill running on the schizophrenia-related behaviors. Consistently, chemogenetic activation of these interneurons improved neurogenesis and alleviated the schizophrenia-related behaviors. These results suggest a pivotal role of PV-positive interneuron-mediated adult neurogenesis in exercise. (3) However, schizophrenia-related behavioral phenotypes and adult neurogenesis in the DG could still be reversed by exercise after specifically knocking out the schizophrenia-related gene ErbB4 in PV interneurons, as a means to reduce their GABA release. These results suggest that activation of PV interneurons in the DG is sufficient for treadmill running to reverse schizophrenia-like phenotypes.
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Affiliation(s)
- Yandong Yi
- Department of Physiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China.,Department of Pharmacy, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanlong Song
- Department of Physiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China.,Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China
| | - Yisheng Lu
- Department of Physiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China.,Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China
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13
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Lucchese G, Stahl B. Peptide Sharing Between Viruses and DLX Proteins: A Potential Cross-Reactivity Pathway to Neuropsychiatric Disorders. Front Neurosci 2018; 12:150. [PMID: 29618965 PMCID: PMC5871705 DOI: 10.3389/fnins.2018.00150] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Accepted: 02/26/2018] [Indexed: 12/24/2022] Open
Abstract
The present study seeks to determine potential associations between viral infections and neuropsychiatric diseases. To address this issue, we investigated the peptide commonalities between viruses that have been related to psychiatric and neurological disorders—such as rubella, human immunodeficiency virus, and herpesviruses—and human distal-less homeobox (DLX) proteins expressed in developing brain—namely, DLX1, DLX2, DLX5, and DLX6. Peptide matching analyses revealed a high degree of pentapeptide sharing. From an immunological perspective, this overlap is relevant because pentapeptides are endowed with immunogenicity and antigenicity—that is, they are immune determinants. Moreover, infection-induced immune cross-reactions might have functional, spatial, and temporal implications related to the functions and expression patterns of DLX1 and DLX5 in the fetal and adult human brain. In sum, our data support the hypothesis that viral infections may be linked to neuropsychiatric diseases through autoimmune cross-reactions caused by molecular mimicry between viral proteins and brain-specific DLX self-antigens.
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Affiliation(s)
- Guglielmo Lucchese
- Brain Language Laboratory, Freie Universität Berlin, Berlin, Germany.,Department of Neurology, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Benjamin Stahl
- Department of Neurology, Universitätsmedizin Greifswald, Greifswald, Germany.,Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.,Department of Neurophysics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.,Psychologische Hochschule Berlin, Berlin, Germany
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14
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Takai Y, Kawai M, Ogo T, Ichinose T, Furuya S, Takaki N, Tone Y, Udo H, Furuse M, Yasuo S. Early-life Photoperiod Influences Depression-like Behavior, Prepulse Inhibition of the Acoustic Startle Response, and Hippocampal Astrogenesis in Mice. Neuroscience 2018; 374:133-143. [DOI: 10.1016/j.neuroscience.2018.01.038] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 01/18/2018] [Indexed: 10/18/2022]
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15
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Hu W, Lin D, Cao S, Liu J, Chen J, Calhoun VD, Wang YP. Adaptive Sparse Multiple Canonical Correlation Analysis With Application to Imaging (Epi)Genomics Study of Schizophrenia. IEEE Trans Biomed Eng 2018; 65:390-399. [PMID: 29364120 PMCID: PMC5826588 DOI: 10.1109/tbme.2017.2771483] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Finding correlations across multiple data sets in imaging and (epi)genomics is a common challenge. Sparse multiple canonical correlation analysis (SMCCA) is a multivariate model widely used to extract contributing features from each data while maximizing the cross-modality correlation. The model is achieved by using the combination of pairwise covariances between any two data sets. However, the scales of different pairwise covariances could be quite different and the direct combination of pairwise covariances in SMCCA is unfair. The problem of "unfair combination of pairwise covariances" restricts the power of SMCCA for feature selection. In this paper, we propose a novel formulation of SMCCA, called adaptive SMCCA, to overcome the problem by introducing adaptive weights when combining pairwise covariances. Both simulation and real-data analysis show the outperformance of adaptive SMCCA in terms of feature selection over conventional SMCCA and SMCCA with fixed weights. Large-scale numerical experiments show that adaptive SMCCA converges as fast as conventional SMCCA. When applying it to imaging (epi)genetics study of schizophrenia subjects, we can detect significant (epi)genetic variants and brain regions, which are consistent with other existing reports. In addition, several significant brain-development related pathways, e.g., neural tube development, are detected by our model, demonstrating imaging epigenetic association may be overlooked by conventional SMCCA. All these results demonstrate that adaptive SMCCA are well suited for detecting three-way or multiway correlations and thus can find widespread applications in multiple omics and imaging data integration.
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Affiliation(s)
- Wenxing Hu
- Biomedical Engineering Department, Tulane University, New Orleans, LA 70118, USA
| | - Dongdong Lin
- Mind Research Network and Dept. of ECE, University of New Mexico, Albuquerque, NM, 87106
| | - Shaolong Cao
- Department of Bioinformatics & Computational Biology, UT MD Anderson Cancer Center, Houston, TX
| | - Jingyu Liu
- Mind Research Network and Dept. of ECE, University of New Mexico, Albuquerque, NM, 87106
| | - Jiayu Chen
- Mind Research Network and Dept. of ECE, University of New Mexico, Albuquerque, NM, 87106
| | - Vince D. Calhoun
- Mind Research Network and Dept. of ECE, University of New Mexico, Albuquerque, NM, 87106
| | - Yu-Ping Wang
- Biomedical Engineering Department, Tulane University, New Orleans, LA 70118, USA
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16
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Adachi N, Akanuma N, Fenwick P, Ito M, Okazaki M, Ishida S, Sekimoto M, Kato M, Onuma T. Seizure activity and individual vulnerability on first-episode interictal psychosis in epilepsy. Epilepsy Behav 2018; 79:234-238. [PMID: 29249448 DOI: 10.1016/j.yebeh.2017.10.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 10/07/2017] [Indexed: 10/18/2022]
Abstract
OBJECTIVE Despite a theoretical consensus that interictal psychosis (IIP) is related to various epilepsy-related factors, the impact of seizure activity on development of IIP remains inconclusive. This is the first controlled study using quantitative seizure-activity measures at the onset of IIP. METHODS One hundred and eighty-one patients with epilepsy who exhibited first-episode IIP (IIP group) and 427 patients with epilepsy without psychotic episodes (control group) were enrolled. The control group was matched for age, epilepsy type, and duration of epilepsy. The two seizure-activity indices (seizure frequency at the time of onset of first-episode IIP and the number of seizures before the onset of IIP) were evaluated and compared between the IIP and control groups. Logistic regression analysis was used for extracting risk variables to develop first-episode IIP. RESULTS The sum of previous seizures was greater in the IIP than in control groups. This was particularly the case in the patients with partial epilepsies (PE). Higher seizure frequency in the patients with PE was associated with the development of first-episode IIP while no association was found in the whole cohort or in the patients with generalized epilepsies (GE). Subsequent multivariate analysis revealed the sum of previous seizures and family history of psychosis as risk variables to first-episode IIP. CONCLUSIONS The accumulation of seizure-related damages and family history of psychosis is associated with the onset of IIP episodes, particularly in the patients with PE. Seizure activity and individual vulnerability to psychosis are likely to be interacted for as the development of IIP in patients with epilepsy.
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Affiliation(s)
- Naoto Adachi
- National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; Adachi Mental Clinic, Sapporo, Japan.
| | - Nozomi Akanuma
- National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; South London & Maudsley NHS Foundation Trust, London, UK
| | - Peter Fenwick
- South London & Maudsley NHS Foundation Trust, London, UK.
| | - Masumi Ito
- National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; Jozen Clinic, Sapporo, Japan.
| | - Mitsutoshi Okazaki
- National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
| | - Shiro Ishida
- National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
| | - Masanori Sekimoto
- National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; Musashino Kokubunji Clinic, Tokyo, Japan.
| | - Masaaki Kato
- National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; Musashino Kokubunji Clinic, Tokyo, Japan.
| | - Teiichi Onuma
- National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; Musashino Kokubunji Clinic, Tokyo, Japan.
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17
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Chikama K, Yamada H, Tsukamoto T, Kajitani K, Nakabeppu Y, Uchimura N. Chronic atypical antipsychotics, but not haloperidol, increase neurogenesis in the hippocampus of adult mouse. Brain Res 2017; 1676:77-82. [DOI: 10.1016/j.brainres.2017.09.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 08/31/2017] [Accepted: 09/04/2017] [Indexed: 11/28/2022]
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18
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19
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20
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Bettio LEB, Rajendran L, Gil-Mohapel J. The effects of aging in the hippocampus and cognitive decline. Neurosci Biobehav Rev 2017; 79:66-86. [PMID: 28476525 DOI: 10.1016/j.neubiorev.2017.04.030] [Citation(s) in RCA: 404] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 03/15/2017] [Accepted: 04/10/2017] [Indexed: 02/06/2023]
Abstract
Aging is a natural process that is associated with cognitive decline as well as functional and social impairments. One structure of particular interest when considering aging and cognitive decline is the hippocampus, a brain region known to play an important role in learning and memory consolidation as well as in affective behaviours and mood regulation, and where both functional and structural plasticity (e.g., neurogenesis) occur well into adulthood. Neurobiological alterations seen in the aging hippocampus including increased oxidative stress and neuroinflammation, altered intracellular signalling and gene expression, as well as reduced neurogenesis and synaptic plasticity, are thought to be associated with age-related cognitive decline. Non-invasive strategies such as caloric restriction, physical exercise, and environmental enrichment have been shown to counteract many of the age-induced alterations in hippocampal signalling, structure, and function. Thus, such approaches may have therapeutic value in counteracting the deleterious effects of aging and protecting the brain against age-associated neurodegenerative processes.
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Affiliation(s)
- Luis E B Bettio
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Luckshi Rajendran
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Joana Gil-Mohapel
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada; UBC Island Medical program, University of Victoria, Victoria, BC, Canada.
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21
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Mattei D, Ivanov A, Ferrai C, Jordan P, Guneykaya D, Buonfiglioli A, Schaafsma W, Przanowski P, Deuther-Conrad W, Brust P, Hesse S, Patt M, Sabri O, Ross TL, Eggen BJL, Boddeke EWGM, Kaminska B, Beule D, Pombo A, Kettenmann H, Wolf SA. Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment. Transl Psychiatry 2017; 7:e1120. [PMID: 28485733 PMCID: PMC5534948 DOI: 10.1038/tp.2017.80] [Citation(s) in RCA: 167] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 02/04/2017] [Accepted: 02/23/2017] [Indexed: 12/14/2022] Open
Abstract
Maternal immune activation (MIA) during pregnancy has been linked to an increased risk of developing psychiatric pathologies in later life. This link may be bridged by a defective microglial phenotype in the offspring induced by MIA, as microglia have key roles in the development and maintenance of neuronal signaling in the central nervous system. The beneficial effects of the immunomodulatory treatment with minocycline on schizophrenic patients are consistent with this hypothesis. Using the MIA mouse model, we found an altered microglial transcriptome and phagocytic function in the adult offspring accompanied by behavioral abnormalities. The changes in microglial phagocytosis on a functional and transcriptional level were similar to those observed in a mouse model of Alzheimer's disease hinting to a related microglial phenotype in neurodegenerative and psychiatric disorders. Minocycline treatment of adult MIA offspring reverted completely the transcriptional, functional and behavioral deficits, highlighting the potential benefits of therapeutic targeting of microglia in psychiatric disorders.
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Affiliation(s)
- D Mattei
- Cellular Neurocience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - A Ivanov
- Core Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany,Charite Medical University, Berlin, Germany
| | - C Ferrai
- Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - P Jordan
- Cellular Neurocience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - D Guneykaya
- Cellular Neurocience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - A Buonfiglioli
- Cellular Neurocience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany,Institute of Cell Biology and Neurobiology, Charité-Universitaetsmedizin, Berlin, Germany
| | - W Schaafsma
- Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - P Przanowski
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - W Deuther-Conrad
- Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig, Germany
| | - P Brust
- Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig, Germany
| | - S Hesse
- Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany,Integrated Treatment and Research Centre (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany
| | - M Patt
- Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany
| | - O Sabri
- Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany
| | - T L Ross
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | - B J L Eggen
- Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - E W G M Boddeke
- Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - B Kaminska
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - D Beule
- Core Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany,Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - A Pombo
- Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - H Kettenmann
- Cellular Neurocience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - S A Wolf
- Cellular Neurocience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany,Cellular Neurocience, Max-Delbrück-Center of Molecular Medicine in the Helmholtz Association, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. E-mail:
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22
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Hueston CM, Cryan JF, Nolan YM. Stress and adolescent hippocampal neurogenesis: diet and exercise as cognitive modulators. Transl Psychiatry 2017; 7:e1081. [PMID: 28375209 PMCID: PMC5416690 DOI: 10.1038/tp.2017.48] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 01/04/2017] [Accepted: 02/01/2017] [Indexed: 02/08/2023] Open
Abstract
Adolescence is a critical period for brain maturation. Deciphering how disturbances to the central nervous system at this time affect structure, function and behavioural outputs is important to better understand any long-lasting effects. Hippocampal neurogenesis occurs during development and continues throughout life. In adulthood, integration of these new cells into the hippocampus is important for emotional behaviour, cognitive function and neural plasticity. During the adolescent period, maturation of the hippocampus and heightened levels of hippocampal neurogenesis are observed, making alterations to neurogenesis at this time particularly consequential. As stress negatively affects hippocampal neurogenesis, and adolescence is a particularly stressful time of life, it is important to investigate the impact of stressor exposure at this time on hippocampal neurogenesis and cognitive function. Adolescence may represent not only a time for which stress can have long-lasting effects, but is also a critical period during which interventions, such as exercise and diet, could ameliorate stress-induced changes to hippocampal function. In addition, intervention at this time may also promote life-long behavioural changes that would aid in fostering increased hippocampal neurogenesis and cognitive function. This review addresses both the acute and long-term stress-induced alterations to hippocampal neurogenesis and cognition during the adolescent period, as well as changes to the stress response and pubertal hormones at this time which may result in differential effects than are observed in adulthood. We hypothesise that adolescence may represent an optimal time for healthy lifestyle changes to have a positive and long-lasting impact on hippocampal neurogenesis, and to protect against stress-induced deficits. We conclude that future research into the mechanisms underlying the susceptibility of the adolescent hippocampus to stress, exercise and diet and the consequent effect on cognition may provide insight into why adolescence may be a vital period for correct conditioning of future hippocampal function.
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Affiliation(s)
- C M Hueston
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - J F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Y M Nolan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
- APC Microbiome Institute, University College Cork, Cork, Ireland
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Productive infection of human neural progenitor cells by R5 tropic HIV-1: opiate co-exposure heightens infectivity and functional vulnerability. AIDS 2017; 31:753-764. [PMID: 28099189 DOI: 10.1097/qad.0000000000001398] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE HIV type-1 (HIV-1) causes a spectrum of central nervous system (CNS) complications; many are worsened by opiate co-exposure. Human neural progenitor cells (hNPCs) give rise to all CNS neurons and macroglia. We tested the hypothesis that hNPC maturation and fate are altered by HIV and opiates, contributing to HIV-1-related neuropathology. Reports of hNPC infection remain controversial. We rigorously examined this question, testing whether hNPCs propogated infection, and whether HIV affected hNPCs absent their infection. DESIGN AND METHODS Primary hNPCs were characterized over multiple passages. Following R5 HIV-1BaL exposure, p24, Nef, and tat assays monitored infection; a serial dilution approach tested infection transfer to naive hNPCs. Bromodeoxyuridine uptake, population doubling time, and immunostaining assessed proliferation and differentiation. Morphine co-exposure assessed opiate interactions. Supernatant from HIV-1BaL-infected PBMCs (HIVsup), HIV-1BaL, and ultraviolet light-inactivated HIVsup were compared to test effects of inflammatory milieu versus virus or infection per se. RESULTS The hNPCs (CD4/CD8/Iba/CXC3CL1/CD11b) were infectable and could transfer infection to naive hNPCs. Infection was partly blocked by maraviroc, implicating CCR5. HIVsup reduced hNPC proliferation and caused premature differentiation into neurons/astroglia. Effects on proliferation were due to soluble factors/viral proteins, not infection per se. Morphine co-exposure exacerbated certain functional consequences of HIVsup, and sustained the infection of hNPCs. CONCLUSION hNPCs can be infected and propagate virus in vitro. hNPCs or their progeny may represent an underappreciated viral reservoir. Factors from infected cells alter hNPC proliferation and neural cell maturation, which likely compromises CNS structure and function. Morphine-HIV interactions may worsen dysfunction and sustain infection.
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Mansouri S, Agartz I, Ögren SO, Patrone C, Lundberg M. PACAP Protects Adult Neural Stem Cells from the Neurotoxic Effect of Ketamine Associated with Decreased Apoptosis, ER Stress and mTOR Pathway Activation. PLoS One 2017; 12:e0170496. [PMID: 28125634 PMCID: PMC5268395 DOI: 10.1371/journal.pone.0170496] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 01/05/2017] [Indexed: 12/15/2022] Open
Abstract
Ketamine administration is a well-established approach to mimic experimentally some aspects of schizophrenia. Adult neurogenesis dysregulation is associated with psychiatric disorders, including schizophrenia. The potential role of neurogenesis in the ketamine-induced phenotype is largely unknown. Recent results from human genetic studies have shown the pituitary adenylate cyclase-activating polypeptide (PACAP) gene is a risk factor for schizophrenia. Its potential role on the regulation of neurogenesis in experimental model of schizophrenia remains to be investigated. We aimed to determine whether ketamine affects the viability of adult neural stem cells (NSC). We also investigated whether the detrimental effect mediated by ketamine could be counteracted by PACAP. NSCs were isolated from the subventricular zone of the mouse and exposed to ketamine with/without PACAP. After 24 hours, cell viability, potential involvement of apoptosis, endoplasmic reticulum (ER) stress, mTOR and AMPA pathway activation were assessed by quantitative RT-PCR and Western blot analysis. We show that ketamine impairs NSC viability in correlation with increased apoptosis, ER stress and mTOR activation. The results also suggest that the effect of ketamine occurs via AMPA receptor activation. Finally, we show that PACAP counteracted the decreased NSC viability induced by ketamine via the specific activation of the PAC-1 receptor subtype. Our study shows that the NSC viability may be negatively affected by ketamine with putative importance for the development of a schizophrenia phenotype in the ketamine induced animal model of schizophrenia. The neuroprotective effect via PAC-1 activation suggests a potentially novel pharmacological target for the treatment of schizophrenia, via neurogenesis normalization.
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Affiliation(s)
- Shiva Mansouri
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
- * E-mail:
| | - Ingrid Agartz
- Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Norway
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Sven-Ove Ögren
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Cesare Patrone
- Department of Clinical Science and Education, Södersjukhuset, Internal medicine, Karolinska Institutet, Stockholm, Sweden
| | - Mathias Lundberg
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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O'Leary JD, O'Leary OF, Cryan JF, Nolan YM. Regulation of behaviour by the nuclear receptor TLX. GENES BRAIN AND BEHAVIOR 2016; 17:e12357. [PMID: 27790850 DOI: 10.1111/gbb.12357] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 09/15/2016] [Accepted: 10/25/2016] [Indexed: 01/10/2023]
Abstract
The orphan nuclear receptor Tlx (Nr2e1) is a key regulator of both embryonic and adult hippocampal neurogenesis. Several different mouse models have been developed which target Tlx in vivo including spontaneous deletion models (from birth) and targeted and conditional knockouts. Although some conflicting findings have been reported, for the most part studies have demonstrated that Tlx is important in regulating processes that underlie neurogenesis, spatial learning, anxiety-like behaviour and interestingly, aggression. More recent data have demonstrated that disrupting Tlx during early life induces hyperactivity and that Tlx plays a role in emotional regulation. Moreover, there are sex- and age-related differences in some behaviours in Tlx knockout mice during adolescence and adulthood. Here, we discuss the role of Tlx in motor-, cognitive-, aggressive- and anxiety-related behaviours during adolescence and adulthood. We examine current evidence which provides insight into Tlx during neurodevelopment, and offer our thoughts on the function of Tlx in brain and behaviour. We further hypothesize that Tlx is a key target in understanding the emergence of neurobiological disorders during adolescence and early adulthood.
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Affiliation(s)
- J D O'Leary
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - O F O'Leary
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.,APC Microbiome Institute, University College Cork, Cork, Ireland
| | - J F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.,APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Y M Nolan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
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26
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Does cannabidiol have a role in the treatment of schizophrenia? Schizophr Res 2016; 176:281-290. [PMID: 27374322 DOI: 10.1016/j.schres.2016.06.022] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 06/15/2016] [Accepted: 06/17/2016] [Indexed: 01/08/2023]
Abstract
Schizophrenia is a debilitating psychiatric disorder which places a significant emotional and economic strain on the individual and society-at-large. Unfortunately, currently available therapeutic strategies do not provide adequate relief and some patients are treatment-resistant. In this regard, cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, has shown significant promise as a potential antipsychotic for the treatment of schizophrenia. However, there is still considerable uncertainty about the mechanism of action of CBD as well as the brain regions which are thought to mediate its putative antipsychotic effects. We argue that further research on CBD is required to fast-track its progress to the clinic and in doing so, we may generate novel insights into the neurobiology of schizophrenia.
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Khan MM. Neurocognitive, Neuroprotective, and Cardiometabolic Effects of Raloxifene: Potential for Improving Therapeutic Outcomes in Schizophrenia. CNS Drugs 2016; 30:589-601. [PMID: 27193386 DOI: 10.1007/s40263-016-0343-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Raloxifene is a selective estrogen receptor modulator that has been approved for treating osteoporosis and breast cancer in high-risk postmenopausal women. However, recent evidence suggests that raloxifene adjunct therapy improves cognition and reduces symptom severity in men and women with schizophrenia. In animal models, raloxifene increases forebrain neurogenesis and enhances working memory and synaptic plasticity. It may consequently repair the neuronal and synaptic connectivity that is disrupted in schizophrenia. It also reduces oxidative stress and neuroinflammation, which are potent etiological factors in the neuropathology of schizophrenia. Furthermore, in postmenopausal women, raloxifene reduces the risks for atherosclerosis, diabetes mellitus, and weight gain, which are serious adverse effects associated with long-term antipsychotic treatment in schizophrenia; therefore, it may improve the safety and efficacy of antipsychotic drugs. In this review, recent insights into the neurocognitive, neuroprotective, and cardiometabolic effects of raloxifene in relation to therapeutic outcomes in schizophrenia are discussed.
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Affiliation(s)
- Mohammad M Khan
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Zawia, Jamal Abdul Nassre Street, P.O. Box 16418, Az-Zawiyah, Libya.
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Glucocorticoids Suppress the Protective Effect of Cyclooxygenase-2-Related Signaling on Hippocampal Neurogenesis Under Acute Immune Stress. Mol Neurobiol 2016; 54:1953-1966. [PMID: 26910812 DOI: 10.1007/s12035-016-9766-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 02/01/2016] [Indexed: 01/12/2023]
Abstract
Stress and glucocorticoids suppress adult neurogenesis in the hippocampus. However, the molecular mechanisms underlying stress-induced impairment of adult neurogenesis are poorly understood. We previously suggested that cyclooxygenase (COX)-2 is a common mediator of stresses in the brain. Here, using a lipopolysaccharide (LPS)-induced acute infectious stress model, we evaluated the roles of COX-2 and its major downstream product prostaglandin E2 (PGE2) in adult neurogenesis and the influence of glucocorticoids on COX-2-related signaling. Treatment of rats with LPS significantly decreased neurogenesis in the dentate gyrus (DG) of the hippocampus, and this inhibitory effect of LPS on neurogenesis was reversed by the glucocorticoid receptor antagonist RU486. Moreover, RU486 significantly enhanced the increase in messenger RNA (mRNA) levels of COX-2 and microsomal prostaglandin E synthase (mPGES)-1 in the hippocampus following LPS stimulation. Administration of AH6809, a selective antagonist of the PGE2 EP2 receptor, as well as NS398, a COX-2 selective inhibitor, exacerbated the suppression of proliferation of neural progenitor cells (NPCs) in the DG. Gene expression of EP1, EP2, and EP3, but not EP4, receptors was also increased following LPS stimulation. Immunohistochemical studies indicated that NPCs expressed EP2 receptor, whereas the majority of cells expressing COX-2 and mPGES-1 were mature neurons in the DG. These results suggest that acute infectious stress upregulates COX-2-related signaling in neurons in the DG, which plays a protective role in neurogenesis through EP2 receptor at least partially. In addition, LPS-induced glucocorticoids suppress this COX-2-related signaling, resulting in decreased neurogenesis.
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29
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Wright C, Gupta CN, Chen J, Patel V, Calhoun VD, Ehrlich S, Wang L, Bustillo JR, Perrone-Bizzozero NI, Turner JA. Polymorphisms in MIR137HG and microRNA-137-regulated genes influence gray matter structure in schizophrenia. Transl Psychiatry 2016; 6:e724. [PMID: 26836412 PMCID: PMC4872419 DOI: 10.1038/tp.2015.211] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 10/06/2015] [Accepted: 10/09/2015] [Indexed: 02/06/2023] Open
Abstract
Evidence suggests that microRNA-137 (miR-137) is involved in the genetic basis of schizophrenia. Risk variants within the miR-137 host gene (MIR137HG) influence structural and functional brain-imaging measures, and miR-137 itself is predicted to regulate hundreds of genes. We evaluated the influence of a MIR137HG risk variant (rs1625579) in combination with variants in miR-137-regulated genes TCF4, PTGS2, MAPK1 and MAPK3 on gray matter concentration (GMC). These genes were selected based on our previous work assessing schizophrenia risk within possible miR-137-regulated gene sets using the same cohort of subjects. A genetic risk score (GRS) was determined based on genotypes of these four schizophrenia risk-associated genes in 221 Caucasian subjects (89 schizophrenia patients and 132 controls). The effects of the rs1625579 genotype with the GRS of miR-137-regulated genes in a three-way interaction with diagnosis on GMC patterns were assessed using a multivariate analysis. We found that schizophrenia subjects homozygous for the MIR137HG risk allele show significant decreases in occipital, parietal and temporal lobe GMC with increasing miR-137-regulated GRS, whereas those carrying the protective minor allele show significant increases in GMC with GRS. No correlations of GMC and GRS were found in control subjects. Variants within or upstream of genes regulated by miR-137 in combination with the MIR137HG risk variant may influence GMC in schizophrenia-related regions in patients. Given that the genes evaluated here are involved in protein kinase A signaling, dysregulation of this pathway through alterations in miR-137 biogenesis may underlie the gray matter loss seen in the disease.
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Affiliation(s)
- C Wright
- The Mind Research Network, Albuquerque, NM, USA
- Department of Neurosciences, University of New Mexico, Albuquerque, NM, USA
| | - C N Gupta
- The Mind Research Network, Albuquerque, NM, USA
| | - J Chen
- The Mind Research Network, Albuquerque, NM, USA
| | - V Patel
- The Mind Research Network, Albuquerque, NM, USA
| | - V D Calhoun
- The Mind Research Network, Albuquerque, NM, USA
- Department of Neurosciences, University of New Mexico, Albuquerque, NM, USA
- Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM, USA
| | - S Ehrlich
- Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität, Dresden, Germany
- Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA
| | - L Wang
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - J R Bustillo
- Department of Neurosciences, University of New Mexico, Albuquerque, NM, USA
- Department of Psychiatry and Behavioral Sciences, University of New Mexico, Albuquerque, NM, USA
| | - N I Perrone-Bizzozero
- Department of Neurosciences, University of New Mexico, Albuquerque, NM, USA
- Department of Psychiatry and Behavioral Sciences, University of New Mexico, Albuquerque, NM, USA
| | - J A Turner
- The Mind Research Network, Albuquerque, NM, USA
- Department of Psychology and Neuroscience Institute, Georgia State University, Atlanta, GA, USA
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30
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Scharfman HE, Bernstein HL. Potential implications of a monosynaptic pathway from mossy cells to adult-born granule cells of the dentate gyrus. Front Syst Neurosci 2015; 9:112. [PMID: 26347618 PMCID: PMC4541026 DOI: 10.3389/fnsys.2015.00112] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 07/20/2015] [Indexed: 11/13/2022] Open
Abstract
The dentate gyrus (DG) is important to many aspects of hippocampal function, but there are many aspects of the DG that are incompletely understood. One example is the role of mossy cells (MCs), a major DG cell type that is glutamatergic and innervates the primary output cells of the DG, the granule cells (GCs). MCs innervate the GCs as well as local circuit neurons that make GABAergic synapses on GCs, so the net effect of MCs on GCs – and therefore the output of the DG – is unclear. Here we first review fundamental information about MCs and the current hypotheses for their role in the normal DG and in diseases that involve the DG. Then we review previously published data which suggest that MCs are a source of input to a subset of GCs that are born in adulthood (adult-born GCs). In addition, we discuss the evidence that adult-born GCs may support the normal inhibitory ‘gate’ functions of the DG, where the GCs are a filter or gate for information from the entorhinal cortical input to area CA3. The implications are then discussed in the context of seizures and temporal lobe epilepsy (TLE). In TLE, it has been suggested that the DG inhibitory gate is weak or broken and MC loss leads to insufficient activation of inhibitory neurons, causing hyperexcitability. That idea was called the “dormant basket cell hypothesis.” Recent data suggest that loss of normal adult-born GCs may also cause disinhibition, and seizure susceptibility. Therefore, we propose a reconsideration of the dormant basket cell hypothesis with an intervening adult-born GC between the MC and basket cell and call this hypothesis the “dormant immature granule cell hypothesis.”
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Affiliation(s)
- Helen E Scharfman
- The Nathan Kline Institute for Psychiatric Research, Orangeburg NY, USA ; New York University Langone Medical Center, New York NY, USA
| | - Hannah L Bernstein
- The Nathan Kline Institute for Psychiatric Research, Orangeburg NY, USA ; New York University Langone Medical Center, New York NY, USA
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31
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Lee H, Kang E, GoodSmith D, Yoon DY, Song H, Knierim JJ, Ming GL, Christian KM. DISC1-mediated dysregulation of adult hippocampal neurogenesis in rats. Front Syst Neurosci 2015; 9:93. [PMID: 26161071 PMCID: PMC4479724 DOI: 10.3389/fnsys.2015.00093] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 06/01/2015] [Indexed: 01/14/2023] Open
Abstract
Adult hippocampal neurogenesis, the constitutive generation of new granule cells in the dentate gyrus of the mature brain, is a robust model of neural development and its dysregulation has been implicated in the pathogenesis of psychiatric and neurological disorders. Previous studies in mice have shown that altered expression of Disrupted-In-Schizophrenia 1 (Disc1), the mouse homolog of a risk gene for major psychiatric disorders, results in several distinct morphological phenotypes during neuronal development. Although there are advantages to using rats over mice for neurophysiological studies, genetic manipulations have not been widely utilized in rat models. Here, we used a retroviral-mediated approach to knockdown DISC1 expression in dividing cells in the rat dentate gyrus and characterized the morphological development of adult-born granule neurons. Consistent with earlier findings in mice, we show that DISC1 knockdown in adult-born dentate granule cells in rats resulted in accelerated dendritic growth, soma hypertrophy, ectopic dendrites, and mispositioning of new granule cells due to overextended migration. Our study thus demonstrates that the Disc1 genetic manipulation approach used in prior mouse studies is feasible in rats and that there is a conserved biological function of this gene across species. Extending gene-based studies of adult hippocampal neurogenesis from mice to rats will allow for the development of additional models that may be more amenable to behavioral and in vivo electrophysiological investigations. These models, in turn, can generate additional insight into the systems-level mechanisms of how risk genes for complex psychiatric disorders may impact adult neurogenesis and hippocampal function.
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Affiliation(s)
- Heekyung Lee
- Krieger Mind/Brain Institute, Johns Hopkins University Baltimore, MD, USA
| | - Eunchai Kang
- Institute for Cell Engineering, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Neurology, Johns Hopkins University School of Medicine Baltimore, MD, USA
| | - Douglas GoodSmith
- Krieger Mind/Brain Institute, Johns Hopkins University Baltimore, MD, USA
| | - Do Yeon Yoon
- Department of Neurology, Johns Hopkins University School of Medicine Baltimore, MD, USA
| | - Hongjun Song
- Institute for Cell Engineering, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Neurology, Johns Hopkins University School of Medicine Baltimore, MD, USA ; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine Baltimore, MD, USA
| | - James J Knierim
- Krieger Mind/Brain Institute, Johns Hopkins University Baltimore, MD, USA ; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine Baltimore, MD, USA
| | - Guo-Li Ming
- Institute for Cell Engineering, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Neurology, Johns Hopkins University School of Medicine Baltimore, MD, USA ; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine Baltimore, MD, USA
| | - Kimberly M Christian
- Institute for Cell Engineering, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Neurology, Johns Hopkins University School of Medicine Baltimore, MD, USA
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Chou S, Jones S, Li M. Adolescent olanzapine sensitization is correlated with hippocampal stem cell proliferation in a maternal immune activation rat model of schizophrenia. Brain Res 2015; 1618:122-35. [PMID: 26049127 DOI: 10.1016/j.brainres.2015.05.036] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Revised: 05/09/2015] [Accepted: 05/14/2015] [Indexed: 12/12/2022]
Abstract
Previous work established that repeated olanzapine (OLZ) administration in normal adolescent rats induces a sensitization effect (i.e. increased behavioral responsiveness to drug re-exposure) in the conditioned avoidance response (CAR) model. However, it is unclear whether the same phenomenon can be detected in animal models of schizophrenia. The present study explored the generalizability of OLZ sensitization from healthy animals to a preclinical neuroinflammatory model of schizophrenia in the CAR. Maternal immune activation (MIA) was induced via polyinosinic:polycytidylic acid (PolyI:C) administration into pregnant dams. Behavioral assessments of offspring first identified decreased maternal separation-induced pup ultrasonic vocalizations and increased amphetamine-induced hyperlocomotion in animals prenatally exposed to PolyI:C. In addition, repeated adolescent OLZ administration confirmed the generalizability of the sensitization phenomenon. Using the CAR test, adolescent MIA animals displayed a similar increase in behavioral responsiveness after repeated OLZ exposure during both the repeated drug test days as well as a subsequent challenge test. Neurobiologically, few studies examining the relationship between hippocampal cell proliferation and survival and either antipsychotic exposure or MIA have incorporated concurrent behavioral changes. Thus, the current study also sought to reveal the correlation between OLZ behavioral sensitization in the CAR and hippocampal cell proliferation and survival. 5'-bromodeoxyuridine immunohistochemistry identified a positive correlation between the magnitude of OLZ sensitization (i.e. change in avoidance suppression induced by OLZ across days) and hippocampal cell proliferation. The implications of the relationship between behavioral and neurobiological results are discussed.
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Affiliation(s)
- Shinnyi Chou
- Department of Psychology, University of Nebraska-Lincoln, 238 Burnett Hall, Lincoln, NE 68588-0308, USA
| | - Sean Jones
- Department of Psychology, University of Nebraska-Lincoln, 238 Burnett Hall, Lincoln, NE 68588-0308, USA
| | - Ming Li
- Department of Psychology, University of Nebraska-Lincoln, 238 Burnett Hall, Lincoln, NE 68588-0308, USA.
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Multivariate genetic determinants of EEG oscillations in schizophrenia and psychotic bipolar disorder from the BSNIP study. Transl Psychiatry 2015; 5:e588. [PMID: 26101851 PMCID: PMC4490286 DOI: 10.1038/tp.2015.76] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 04/27/2015] [Accepted: 05/04/2015] [Indexed: 01/18/2023] Open
Abstract
Schizophrenia (SZ) and psychotic bipolar disorder (PBP) are disabling psychiatric illnesses with complex and unclear etiologies. Electroencephalogram (EEG) oscillatory abnormalities in SZ and PBP probands are heritable and expressed in their relatives, but the neurobiology and genetic factors mediating these abnormalities in the psychosis dimension of either disorder are less explored. We examined the polygenic architecture of eyes-open resting state EEG frequency activity (intrinsic frequency) from 64 channels in 105 SZ, 145 PBP probands and 56 healthy controls (HCs) from the multisite BSNIP (Bipolar-Schizophrenia Network on Intermediate Phenotypes) study. One million single-nucleotide polymorphisms (SNPs) were derived from DNA. We assessed eight data-driven EEG frequency activity derived from group-independent component analysis (ICA) in conjunction with a reduced subset of 10,422 SNPs through novel multivariate association using parallel ICA (para-ICA). Genes contributing to the association were examined collectively using pathway analysis tools. Para-ICA extracted five frequency and nine SNP components, of which theta and delta activities were significantly correlated with two different gene components, comprising genes participating extensively in brain development, neurogenesis and synaptogenesis. Delta and theta abnormality was present in both SZ and PBP, while theta differed between the two disorders. Theta abnormalities were also mediated by gene clusters involved in glutamic acid pathways, cadherin and synaptic contact-based cell adhesion processes. Our data suggest plausible multifactorial genetic networks, including novel and several previously identified (DISC1) candidate risk genes, mediating low frequency delta and theta abnormalities in psychoses. The gene clusters were enriched for biological properties affecting neural circuitry and involved in brain function and/or development.
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Kraepelin revisited: schizophrenia from degeneration to failed regeneration. Mol Psychiatry 2015; 20:671-6. [PMID: 25824303 DOI: 10.1038/mp.2015.35] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 02/11/2015] [Accepted: 02/24/2015] [Indexed: 12/18/2022]
Abstract
One hundred years after its conceptual definition as 'Dementia Praecox' by Emil Kraepelin, schizophrenia is still a serious psychiatric illness that affects young adults and leads to disability in at least half of patients. The key treatment issue is partial or non-response, especially of negative symptoms. The illness is also associated with different degrees of cognitive dysfunction, particularly in verbal and working memory; the resulting functional impairment may lead to unemployment and an inability to maintain stable relationships. Patients' cognitive dysfunction led Kraepelin to the assumption that schizophrenia is a form of juvenile dementia caused by a degenerative process of the human brain. Postmortem studies and a plethora of imaging studies do not support the notion of a degenerative process, but such a process is supported by the recently published, largest genome-wide association study on schizophrenia. More than a 100 hits were described, converging on pathways that have a significant role in dopamine metabolism in immune modulation, calcium signalling and synaptic plasticity. This review suggests that research should focus on animal models based on risk genes like transcription factor 4 and study the effects of exposure to environmental stressors relevant for schizophrenia. The use of relevant end points like pre-pulse inhibition or cognitive dysfunction will allow us to gain an understanding of the molecular pathways in schizophrenia and consequently result in improved treatment options, especially for the disabling aspects of this illness.
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Narayanan B, Ethridge LE, O'Neil K, Dunn S, Mathew I, Tandon N, Calhoun VD, Ruaño G, Kocherla M, Windemuth A, Clementz BA, Tamminga CA, Sweeney JA, Keshavan MS, Pearlson GD. Genetic Sources of Subcomponents of Event-Related Potential in the Dimension of Psychosis Analyzed From the B-SNIP Study. Am J Psychiatry 2015; 172:466-78. [PMID: 25615564 PMCID: PMC4455958 DOI: 10.1176/appi.ajp.2014.13101411] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
OBJECTIVE Biological risk factors underlying psychosis are poorly understood. Biological underpinnings of the dimension of psychosis can be derived using genetic associations with intermediate phenotypes such as subcomponents of auditory event-related potentials (ERPs). Various ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder are heritable and are expressed in unaffected relatives, although studies investigating genetic contributions to ERP abnormalities are limited. The authors used a novel parallel independent component analysis (para-ICA) to determine which empirically derived gene clusters are associated with data-driven ERP subcomponents, assuming a complex etiology underlying psychosis. METHOD The authors examined the multivariate polygenic association of ERP subcomponents from 64-channel auditory oddball data in 144 individuals with schizophrenia, 210 psychotic bipolar disorder probands, and 95 healthy individuals from the multisite Bipolar-Schizophrenia Network on Intermediate Phenotypes study. Data were reduced by principal components analysis to two target and one standard ERP waveforms. Multivariate association of compressed ERP waveforms with a set of 20,329 single-nucleotide polymorphisms (SNPs) (reduced from a 1-million-SNP array) was examined using para-ICA. Genes associated with SNPs were further examined using pathway analysis tools. RESULTS Para-ICA identified four ERP components that were significantly correlated with three genetic components. Enrichment analysis revealed complement immune response pathway and multiple processes that significantly mediate ERP abnormalities in psychosis, including synaptic cell adhesion, axon guidance, and neurogenesis. CONCLUSIONS This study identified three genetic components comprising multiple genes mediating ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder. The data suggest a possible polygenic structure comprising genes influencing key neurodevelopmental processes, neural circuitry, and brain function mediating biological pathways plausibly associated with psychosis.
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Affiliation(s)
- Balaji Narayanan
- Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT-06106
| | - Lauren E. Ethridge
- Department of Psychiatry, UT Southwestern Medical School, Dallas, TX-75390
| | - Kasey O'Neil
- Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT-06106
| | - Sabra Dunn
- Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT-06106
| | - Ian Mathew
- Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA-02215 and
| | - Neeraj Tandon
- Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA-02215 and
| | - Vince D. Calhoun
- Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM, 87131,The Mind Research Network, Albuquerque, NM-87106,Departments of Psychiatry & Neurobiology, Yale University School of Medicine, New Haven, CT-06520
| | - Gualberto Ruaño
- Genetics Research Center, Hartford Hospital, Hartford, CT-06106,Genomas Inc, Hartford, CT-06106
| | - Mohan Kocherla
- Genetics Research Center, Hartford Hospital, Hartford, CT-06106,Genomas Inc, Hartford, CT-06106
| | | | | | - Carol A. Tamminga
- Department of Psychiatry, UT Southwestern Medical School, Dallas, TX-75390
| | - John A. Sweeney
- Department of Psychiatry, UT Southwestern Medical School, Dallas, TX-75390
| | - Matcheri S. Keshavan
- Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA-02215 and
| | - Godfrey D. Pearlson
- Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT-06106,Departments of Psychiatry & Neurobiology, Yale University School of Medicine, New Haven, CT-06520
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Duan X, Zhang M, Zhang X, Wang F, Lei M. Molecular modeling and docking study on dopamine D2-like and serotonin 5-HT2A receptors. J Mol Graph Model 2015; 57:143-55. [DOI: 10.1016/j.jmgm.2015.01.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 01/23/2015] [Accepted: 01/29/2015] [Indexed: 01/22/2023]
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Modulating neural plasticity with non-invasive brain stimulation in schizophrenia. Eur Arch Psychiatry Clin Neurosci 2013; 263:621-31. [PMID: 24061608 DOI: 10.1007/s00406-013-0446-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Accepted: 09/02/2013] [Indexed: 12/11/2022]
Abstract
Schizophrenia is a severe mental disorder characterised by a complex phenotype including positive, negative, affective and cognitive symptoms. Various theories have been developed to integrate the clinical phenotype into a strong neurobiological framework. One theory describes schizophrenia as a disorder of impaired neural plasticity. Recently, non-invasive brain stimulation techniques have garnered much attention to their ability to modulate plasticity and treat schizophrenia. The aim of this review is to introduce the basic physiological principles of conventional non-invasive brain stimulation techniques and to review the available evidence for schizophrenia. Despite promising evidence for efficacy in a large number of clinical trials, we continue to have a rudimentary understanding of the underlying neurobiology. Additional investigation is required to improve the response rates to non-invasive brain stimulation, to reduce the interindividual variability and to improve the understanding of non-invasive brain stimulation in schizophrenia.
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Oomen CA, Hvoslef-Eide M, Heath CJ, Mar AC, Horner AE, Bussey TJ, Saksida LM. The touchscreen operant platform for testing working memory and pattern separation in rats and mice. Nat Protoc 2013; 8:2006-21. [PMID: 24051961 PMCID: PMC3982138 DOI: 10.1038/nprot.2013.124] [Citation(s) in RCA: 152] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The automated touchscreen operant chamber for rats and mice allows for the assessment of multiple cognitive domains within the same testing environment. This protocol presents the location discrimination (LD) task and the trial-unique delayed nonmatching-to-location (TUNL) task, which both assess memory for location. During these tasks, animals are trained to a predefined criterion during ∼20-40 daily sessions. In LD sessions, touching the same location on the screen is rewarded on consecutive trials, followed by a reversal of location-reward contingencies. TUNL, a working memory task, requires animals to 'nonmatch' to a sample location after a delay. In both the LD and TUNL tasks, spatial similarity can be varied, allowing assessment of pattern separation ability, a function that is thought to be performed by the dentate gyrus (DG). These tasks are therefore particularly useful in animal models of hippocampal, and specifically DG, function, but they additionally permit discernment of changes in pattern separation from those in working memory.
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Notch signaling activation promotes seizure activity in temporal lobe epilepsy. Mol Neurobiol 2013; 49:633-44. [PMID: 23999872 DOI: 10.1007/s12035-013-8545-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 08/19/2013] [Indexed: 10/26/2022]
Abstract
Notch signaling in the nervous system is often regarded as a developmental pathway. However, recent studies have suggested that Notch is associated with neuronal discharges. Here, focusing on temporal lobe epilepsy, we found that Notch signaling was activated in the kainic acid (KA)-induced epilepsy model and in human epileptogenic tissues. Using an acute model of seizures, we showed that DAPT, an inhibitor of Notch, inhibited ictal activity. In contrast, pretreatment with exogenous Jagged1 to elevate Notch signaling before KA application had proconvulsant effects. In vivo, we demonstrated that the impacts of activated Notch signaling on seizures can in part be attributed to the regulatory role of Notch signaling on excitatory synaptic activity in CA1 pyramidal neurons. In vitro, we found that DAPT treatment impaired synaptic vesicle endocytosis in cultured hippocampal neurons. Taken together, our findings suggest a correlation between aberrant Notch signaling and epileptic seizures. Notch signaling is up-regulated in response to seizure activity, and its activation further promotes neuronal excitation of CA1 pyramidal neurons in acute seizures.
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Panaccione I, Napoletano F, Forte AM, Kotzalidis GD, Del Casale A, Rapinesi C, Brugnoli C, Serata D, Caccia F, Cuomo I, Ambrosi E, Simonetti A, Savoja V, De Chiara L, Danese E, Manfredi G, Janiri D, Motolese M, Nicoletti F, Girardi P, Sani G. Neurodevelopment in schizophrenia: the role of the wnt pathways. Curr Neuropharmacol 2013; 11:535-558. [PMID: 24403877 PMCID: PMC3763761 DOI: 10.2174/1570159x113119990037] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 03/28/2013] [Accepted: 05/12/2013] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES To review the role of Wnt pathways in the neurodevelopment of schizophrenia. METHODS SYSTEMATIC PUBMED SEARCH, USING AS KEYWORDS ALL THE TERMS RELATED TO THE WNT PATHWAYS AND CROSSING THEM WITH EACH OF THE FOLLOWING AREAS: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. RESULTS Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are Akt1, glycogen synthase kinase3beta, and beta-catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. CONCLUSIONS The study of the involvement of Wnt pathway abnormalities in schizophrenia may help in understanding this multifaceted clinical entity; the development of Wnt-related pharmacological targets must await the collection of more data.
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Affiliation(s)
- Isabella Panaccione
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Flavia Napoletano
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Alberto Maria Forte
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Giorgio D. Kotzalidis
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Antonio Del Casale
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Chiara Rapinesi
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Chiara Brugnoli
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Daniele Serata
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Federica Caccia
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Ilaria Cuomo
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Elisa Ambrosi
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Alessio Simonetti
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Valeria Savoja
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Lavinia De Chiara
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Emanuela Danese
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Giovanni Manfredi
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | - Delfina Janiri
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
| | | | - Ferdinando Nicoletti
- NEUROMED, Pozzilli, Isernia, Italy
- Department of Neuropharmacology, Sapienza University, School of Medicine and Pharmacy, Rome, Italy
| | - Paolo Girardi
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
- Centro Lucio Bini, Rome, Italy
| | - Gabriele Sani
- NESMOS Department (Neuroscience, Mental Health, and Sensory Organs), Sapienza University, School of Medicine and Psychology, Sant’Andrea Hospital, Rome, Italy
- Centro Lucio Bini, Rome, Italy
- IRCCS Santa Lucia Foundation, Department of Clinical and Behavioural Neurology, Neuropsychiatry Laboratory, Rome, Italy
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Konefal S, Elliot M, Crespi B. The adaptive significance of adult neurogenesis: an integrative approach. Front Neuroanat 2013; 7:21. [PMID: 23882188 PMCID: PMC3712125 DOI: 10.3389/fnana.2013.00021] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Accepted: 06/18/2013] [Indexed: 01/15/2023] Open
Abstract
Adult neurogenesis in mammals is predominantly restricted to two brain regions, the dentate gyrus (DG) of the hippocampus and the olfactory bulb (OB), suggesting that these two brain regions uniquely share functions that mediate its adaptive significance. Benefits of adult neurogenesis across these two regions appear to converge on increased neuronal and structural plasticity that subserves coding of novel, complex, and fine-grained information, usually with contextual components that include spatial positioning. By contrast, costs of adult neurogenesis appear to center on potential for dysregulation resulting in higher risk of brain cancer or psychological dysfunctions, but such costs have yet to be quantified directly. The three main hypotheses for the proximate functions and adaptive significance of adult neurogenesis, pattern separation, memory consolidation, and olfactory spatial, are not mutually exclusive and can be reconciled into a simple general model amenable to targeted experimental and comparative tests. Comparative analysis of brain region sizes across two major social-ecological groups of primates, gregarious (mainly diurnal haplorhines, visually-oriented, and in large social groups) and solitary (mainly noctural, territorial, and highly reliant on olfaction, as in most rodents) suggest that solitary species, but not gregarious species, show positive associations of population densities and home range sizes with sizes of both the hippocampus and OB, implicating their functions in social-territorial systems mediated by olfactory cues. Integrated analyses of the adaptive significance of adult neurogenesis will benefit from experimental studies motivated and structured by ecologically and socially relevant selective contexts.
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Affiliation(s)
- Sarah Konefal
- Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal General HospitalMontreal, QC, Canada
| | - Mick Elliot
- Department of Biological Sciences, Simon Fraser UniversityBurnaby, BC, Canada
| | - Bernard Crespi
- Department of Biological Sciences, Simon Fraser UniversityBurnaby, BC, Canada
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Ewing SG, Winter C. The ventral portion of the CA1 region of the hippocampus and the prefrontal cortex as candidate regions for neuromodulation in schizophrenia. Med Hypotheses 2013; 80:827-32. [PMID: 23583328 DOI: 10.1016/j.mehy.2013.03.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 03/17/2013] [Indexed: 02/08/2023]
Abstract
Existing antipsychotic drugs are most effective in the treatment of the positive symptoms of schizophrenia. However, they are associated with considerable side effects and have relatively low efficacy. Diminished inhibitory control in the hippocampus has been suggested to lead to hyperactivation of the dopamine system thus underpinning the dopamine-dependent psychosis associated with schizophrenia. Similarly, diminished inhibitory control is thought to underpin the cortical disruption associated with the cognitive dysfunctions. Impairment of a specific class of parvalbumin-positive inhibitory interneuron has been consistently identified in the prefrontal cortex and hippocampus of schizophrenics. Thus, this impairment common to both regions, may subserve these distinct symptom domains. Deep brain stimulation has been suggested to act, at least in part, through the modulation of interneuron function and here we propose the prefrontal cortex and hippocampus as potential targets for neuromodulatory intervention in the treatment of schizophrenia. Further, we specifically consider whether multiple targets and multiple neuromodulatory approaches may be necessary in the treatment of this multi-faceted disease. Finally we propose that deep brain stimulation of the ventral protion of the CA1 region of the hippocampus may be the most promising single target for neuromodulation in schizophrenia.
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Affiliation(s)
- Samuel G Ewing
- Bereich Experimentelle Psychiatrie, Universitätsklinik Carl Gustav Carus an der Technischen Universität Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany.
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TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function. J Neurosci 2013; 32:13987-99. [PMID: 23035106 DOI: 10.1523/jneurosci.2433-12.2012] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Traf2 and NcK interacting kinase (TNiK) contains serine-threonine kinase and scaffold domains and has been implicated in cell proliferation and glutamate receptor regulation in vitro. Here we report its role in vivo using mice carrying a knock-out mutation. TNiK binds protein complexes in the synapse linking it to the NMDA receptor (NMDAR) via AKAP9. NMDAR and metabotropic receptors bidirectionally regulate TNiK phosphorylation and TNiK is required for AMPA expression and synaptic function. TNiK also organizes nuclear complexes and in the absence of TNiK, there was a marked elevation in GSK3β and phosphorylation levels of its cognate phosphorylation sites on NeuroD1 with alterations in Wnt pathway signaling. We observed impairments in dentate gyrus neurogenesis in TNiK knock-out mice and cognitive testing using the touchscreen apparatus revealed impairments in pattern separation on a test of spatial discrimination. Object-location paired associate learning, which is dependent on glutamatergic signaling, was also impaired. Additionally, TNiK knock-out mice displayed hyperlocomotor behavior that could be rapidly reversed by GSK3β inhibitors, indicating the potential for pharmacological rescue of a behavioral phenotype. These data establish TNiK as a critical regulator of cognitive functions and suggest it may play a regulatory role in diseases impacting on its interacting proteins and complexes.
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Castellano O, Arji M, Sancho C, Carro J, Riolobos AS, Molina V, Gómez-Nieto R, de Anchieta de Castro E Horta J, Herrero-Turrión MJ, López DE. Chronic administration of risperidone in a rat model of schizophrenia: a behavioural, morphological and molecular study. Behav Brain Res 2013; 242:178-90. [PMID: 23291154 DOI: 10.1016/j.bbr.2012.12.036] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Revised: 12/18/2012] [Accepted: 12/22/2012] [Indexed: 01/04/2023]
Abstract
In the present work we analyzed the effect of the chronic administration of risperidone (2mg/kg over 65 days) on behavioural, morphological and molecular aspects in an experimental model of schizophrenia obtained by bilateral injection of ibotenic acid into the ventral hippocampus of new-born rats. Our results show that during their adult lives the animals with hippocampal lesions exhibit different alterations, mainly at behavioural level and in the gene expression of dopamine D(2) and 5-HT(2A) receptors. However, at morphological level the study performed on the prefrontal cortex did not reveal any alterations in either the thickness or the number of cells immunoreactive for c-Fos, GFAP, CBP or PV. Overall, risperidone administration elicited a trend towards the recovery of the values previously altered by the hippocampal lesion, approaching the values seen in the animals without lesions. It may be concluded that the administration of risperidone in the schizophrenia model employed helps to improve the altered functions, with no significant negative effects.
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MESH Headings
- Age Factors
- Animals
- Animals, Newborn
- Antipsychotic Agents/administration & dosage
- Avoidance Learning/drug effects
- Avoidance Learning/physiology
- Behavior, Animal/drug effects
- Brain/metabolism
- Brain/pathology
- CREB-Binding Protein/metabolism
- Cell Count
- Disease Models, Animal
- Drug Administration Schedule
- Excitatory Amino Acid Agonists/toxicity
- Exploratory Behavior/drug effects
- Exploratory Behavior/physiology
- Female
- Gene Expression Regulation/drug effects
- Glial Fibrillary Acidic Protein/metabolism
- Grooming/drug effects
- Hippocampus/drug effects
- Hippocampus/physiology
- Ibotenic Acid/toxicity
- Male
- Parvalbumins/metabolism
- Proto-Oncogene Proteins c-fos/metabolism
- Rats
- Rats, Wistar
- Receptor, Serotonin, 5-HT2A/genetics
- Receptor, Serotonin, 5-HT2A/metabolism
- Receptors, Dopamine D2/genetics
- Receptors, Dopamine D2/metabolism
- Risperidone/administration & dosage
- Schizophrenia/chemically induced
- Schizophrenia/drug therapy
- Schizophrenia/physiopathology
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Affiliation(s)
- O Castellano
- Institute for Neuroscience of Castilla y León, Salamanca, Spain; Department of Cell Biology and Pathology, University of Salamanca, Salamanca, Spain.
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45
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Effects of antipsychotics on dentate gyrus stem cell proliferation and survival in animal models: a critical update. Neural Plast 2012; 2012:832757. [PMID: 23150836 PMCID: PMC3488410 DOI: 10.1155/2012/832757] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 09/19/2012] [Accepted: 09/20/2012] [Indexed: 12/15/2022] Open
Abstract
Schizophrenia is a complex psychiatric disorder. Although a number of different hypotheses have been developed to explain its aetiopathogenesis, we are far from understanding it. There is clinical and experimental evidence indicating that neurodevelopmental factors play a major role. Disturbances in neurodevelopment might result in alterations of neuroanatomy and neurochemistry, leading to the typical symptoms observed in schizophrenia. The present paper will critically address the neurodevelopmental models underlying schizophrenia by discussing the effects of typical and atypical antipsychotics in animal models. We will specifically discuss the vitamin D deficiency model, the poly I:C model, the ketamine model, and the postnatal ventral hippocampal lesion model, all of which reflect core neurodevelopmental issues underlying schizophrenia onset.
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46
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Fond G, Macgregor A, Attal J, Larue A, Brittner M, Ducasse D, Capdevielle D. Treating patients with schizophrenia deficit with erythropoietin? Psychiatry Clin Neurosci 2012; 66:375-82. [PMID: 22725970 DOI: 10.1111/j.1440-1819.2012.02359.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This systematic review summarizes and critically appraises the literature on the effect of erythropoietin (EPO) in schizophrenia patients and the pathophysiological mechanisms that may explain the potential of its use in this disease. EPO is mainly known for its regulatory activity in the synthesis of erythrocytes and is frequently used in treatment of chronic anemia. This cytokine, however, has many other properties, some of which may improve the symptoms of psychiatric illness. The review follows the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement guidelines. Three databases (Medline, Web of Science, and Cochrane) were searched combining the search terms 'erythropoietin AND (psychotic disorders OR schizophrenia)'. Seventy-eight studies were included in qualitative synthesis, a meta-analytic approach being prohibited. The findings suggest that several EPO cerebral potential properties may be relevant for schizophrenia treatment, such as neurotransmission regulation, neuroprotection, modulation of inflammation, effects on blood-brain barrier permeability, effects on oxidative stress and neurogenesis. Several potentially detrimental side-effects of EPO therapy, such as increased risk of thrombosis, cancer, increased metabolic rate and mean arterial blood pressure leading to cerebral ischemia could severely limit or halt the use of EPO. Overall, because the available data are inconclusive, further efforts in this field are warranted.
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Affiliation(s)
- Guillaume Fond
- Montpellier University, National Institute for Health and Medical Research, INSERM, Adult Academic Psychiatry Department, La Colombière Hospital/CHRU of Montpellier, Montpellier, France.
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47
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Chen Q, Kogan JH, Gross AK, Zhou Y, Walton NM, Shin R, Heusner CL, Miyake S, Tajinda K, Tamura K, Matsumoto M. SREB2/GPR85, a schizophrenia risk factor, negatively regulates hippocampal adult neurogenesis and neurogenesis-dependent learning and memory. Eur J Neurosci 2012; 36:2597-608. [PMID: 22697179 PMCID: PMC3466408 DOI: 10.1111/j.1460-9568.2012.08180.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
SREB2/GPR85, a member of the super-conserved receptor expressed in brain (SREB) family, is the most conserved G-protein-coupled receptor in vertebrate evolution. Previous human and mouse genetic studies have indicated a possible link between SREB2 and schizophrenia. SREB2 is robustly expressed in the hippocampal formation, especially in the dentate gyrus, a structure with an established involvement in psychiatric disorders and cognition. However, the function of SREB2 in the hippocampus remains elusive. Here we show that SREB2 regulates hippocampal adult neurogenesis, which impacts on cognitive function. Bromodeoxyuridine incorporation and immunohistochemistry were conducted in SREB2 transgenic (Tg, over-expression) and knockout (KO, null-mutant) mice to quantitatively assay adult neurogenesis and newborn neuron dendritic morphology. Cognitive responses associated with adult neurogenesis alteration were evaluated in SREB2 mutant mice. In SREB2 Tg mice, both new cell proliferation and new neuron survival were decreased in the dentate gyrus, whereas an enhancement of new neuron survival occurred in SREB2 KO mouse dentate gyrus. Doublecortin staining revealed dendritic morphology deficits of newly generated neurons in SREB2 Tg mice. In a spatial pattern separation task, SREB2 Tg mice displayed a decreased ability to discriminate spatial relationships, whereas SREB2 KO mice had enhanced abilities in this task. Additionally, SREB2 Tg and KO mice had reciprocal phenotypes in a Y-maze working memory task. Our results indicate that SREB2 is a negative regulator of adult neurogenesis and consequential cognitive functions. Inhibition of SREB2 function may be a novel approach to enhance hippocampal adult neurogenesis and cognitive abilities to ameliorate core symptoms of psychiatric patients.
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Affiliation(s)
- Qian Chen
- CNS, Astellas Research Institute of America LLC, Skokie, IL 60077, USA.
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48
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Bussey TJ, Holmes A, Lyon L, Mar AC, McAllister KAL, Nithianantharajah J, Oomen CA, Saksida LM. New translational assays for preclinical modelling of cognition in schizophrenia: the touchscreen testing method for mice and rats. Neuropharmacology 2012; 62:1191-203. [PMID: 21530550 PMCID: PMC3168710 DOI: 10.1016/j.neuropharm.2011.04.011] [Citation(s) in RCA: 219] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Revised: 04/01/2011] [Accepted: 04/10/2011] [Indexed: 02/02/2023]
Abstract
We describe a touchscreen method that satisfies a proposed 'wish-list' of desirables for a cognitive testing method for assessing rodent models of schizophrenia. A number of tests relevant to schizophrenia research are described which are currently being developed and validated using this method. These tests can be used to study reward learning, memory, perceptual discrimination, object-place associative learning, attention, impulsivity, compulsivity, extinction, simple Pavlovian conditioning, and other constructs. The tests can be deployed using a 'flexible battery' approach to establish a cognitive profile for a particular mouse or rat model. We have found these tests to be capable of detecting not just impairments in function, but enhancements as well, which is essential for testing putative cognitive therapies. New tests are being continuously developed, many of which may prove particularly valuable for schizophrenia research.
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Affiliation(s)
- T J Bussey
- Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK.
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49
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Piontkewitz Y, Bernstein HG, Dobrowolny H, Bogerts B, Weiner I, Keilhoff G. Effects of risperidone treatment in adolescence on hippocampal neurogenesis, parvalbumin expression, and vascularization following prenatal immune activation in rats. Brain Behav Immun 2012; 26:353-63. [PMID: 22154704 DOI: 10.1016/j.bbi.2011.11.004] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 11/18/2011] [Accepted: 11/18/2011] [Indexed: 12/21/2022] Open
Abstract
Maternal infection in pregnancy is an environmental risk factor for the development of schizophrenia and related disorders in the offspring, and this association is recapitulated in animal models using gestational infection or immune stimulation. We have recently shown that behavioral abnormalities and altered hippocampal morphology emerging in adult offspring of dams treated with the viral mimic polyriboinosinic-polyribocytidilic acid (poly I:C) are prevented by treatment with the atypical antipsychotic drug risperidone (RIS) in adolescence. Here we used a battery of cellular markers and Nissl stain to morphometrically analyze different hippocampal cell populations in the offspring of poly I:C and saline-treated mothers that received saline or RIS in adolescence, at different time points of postnatal development. We report that impaired neurogenesis, disturbed micro-vascularization and loss of parvalbumin-expressing hippocampal interneurons, are found in the offspring of poly I:C-treated dams. Most, but not all, of these neuropathological changes are not present in poly I:C offspring that had been treated with RIS. These effects may be part of the complex processes underlying the capacity of RIS treatment in adolescence to prevent structural and behavioral abnormalities deficits in the poly I:C offspring.
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Affiliation(s)
- Yael Piontkewitz
- Department of Psychology, Tel-Aviv University, Tel-Aviv, Israel.
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50
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Schaufelberger MS, Lappin JM, Duran FLS, Rosa PGP, Uchida RR, Santos LC, Murray RM, McGuire PK, Scazufca M, Menezes PR, Busatto GF. Lack of progression of brain abnormalities in first-episode psychosis: a longitudinal magnetic resonance imaging study. Psychol Med 2011; 41:1677-1689. [PMID: 21144111 DOI: 10.1017/s0033291710002163] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Some neuroimaging studies have supported the hypothesis of progressive brain changes after a first episode of psychosis. We aimed to determine whether (i) first-episode psychosis patients would exhibit more pronounced brain volumetric changes than controls over time and (ii) illness course/treatment would relate to those changes. METHOD Longitudinal regional grey matter volume and ventricle:brain ratio differences between 39 patients with first-episode psychosis (including schizophrenia and schizophreniform disorder) and 52 non-psychotic controls enrolled in a population-based case-control study. RESULTS While there was no longitudinal difference in ventricle:brain ratios between first-episode psychosis subjects and controls, patients exhibited grey matter volume changes, indicating a reversible course in the superior temporal cortex and hippocampus compared with controls. A remitting course was related to reversal of baseline temporal grey matter deficits. CONCLUSIONS Our findings do not support the hypothesis of brain changes indicating a progressive course in the initial phase of psychosis. Rather, some brain volume abnormalities may be reversible, possibly associated with a better illness course.
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Affiliation(s)
- M S Schaufelberger
- Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo (USP), São Paulo, Brazil.
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