Better understanding of mechanisms of schizophrenia and bipolar disorder: From human gene expression profiles to mouse models

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Neurobiology of Disease (Impact Factor: 5.08). 09/2011; 45(1):48-56. DOI: 10.1016/j.nbd.2011.08.025
Source: PubMed


The molecular mechanisms of major mental illnesses, such as schizophrenia and bipolar disorder, are unclear. To address this fundamental question, many groups have studied molecular expression profiles in postmortem brains and other tissues from patients compared with those from normal controls. Development of unbiased high-throughput approaches, such as microarray, RNA-seq, and proteomics, have supported and facilitated this endeavor. In addition to genes directly involved in neuron/glia signaling, especially those encoding for synaptic proteins, genes for metabolic cascades are differentially expressed in the brains of patients with schizophrenia and bipolar disorder, compared with those from normal controls in DNA microarray studies. Here we propose the importance and usefulness of genetic mouse models in which such differentially expressed molecules are modulated. These animal models allow us to dissect the mechanisms of how such molecular changes in patient brains may play a role in neuronal circuitries and overall behavioral phenotypes. We also point out that models in which the metabolic genes are modified are obviously untested from mental illness viewpoints, suggesting the potential to re-address these models with behavioral assays and neurochemical assessments.

Download full-text


Available from: Hanna Jaaro-Peled
  • Source
    • "In psychiatric diseases, the nature of molecular and cellular changes of the brain is still obscure (Deep-Soboslay et al. 2011). Notwithstanding recent impressive progress in MRI, genetic and biomarker studies as well as experimental animal research, validation by histological, cellular and molecular research of the human brain is still required (Lin et al. 2011). State of the art imaging techniques , genomics and proteomics make human brain tissue research more compelling than ever. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Research utilizing human tissue and its removal at post-mortem has given rise to many controversies in the media and posed many dilemmas in the fields of law and ethics. The law often lacks clear instructions and unambiguous guidelines. The absence of a harmonized international legislation with regard to post-mortem medical procedures and donation of tissue and organs contributes to the complexity of the issue. Therefore, within the BrainNet Europe (BNE) consortium, a consortium of 19 European brain banks, we drafted an ethical Code of Conduct for brain banking that covers basic legal rules and bioethical principles involved in brain banking. Sources include laws, regulations and guidelines (Declarations, Conventions, Recommendations, Guidelines and Directives) issued by international key organizations, such as the Council of Europe, European Commission, World Medical Association and World Health Organization. The Code of Conduct addresses fundamental topics as the rights of the persons donating their tissue, the obligations of the brain bank with regard to respect and observance of such rights, informed consent, confidentiality, protection of personal data, collections of human biological material and their management, and transparency and accountability within the organization of a brain bank. The Code of Conduct for brain banking is being adopted by the BNE network prior to being enshrined in official legislation for brain banking in Europe and beyond. Electronic supplementary material The online version of this article (doi:10.1007/s00702-014-1353-5) contains supplementary material, which is available to authorized users.
    Preview · Article · Jan 2015 · Journal of Neural Transmission
  • Source
    • "In addition, chromosomal regions, including risk variants show linkage to both BD and SZ (Barnett and Smoller, 2009; Moskvina et al., 2009; Williams et al., 2011a,b). Global gene expression analyses revealed common genes for SZ and BD, which were associated with synapse, neuronal and glial functions, metabolism, cellular and mitochondrial function, nervous system development, immune system development and response, and cell death (Iwamoto et al., 2005; Choi et al., 2008; Shao and Vawter, 2008; Lin et al., 2012). Due to the similarities between both disorders, gene expression profiling of BD and SZ were first compared as one entity to controls to identify common alterations. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric conditions with a neurodevelopmental component. Genetic findings indicate the existence of an overlap in genetic susceptibility across the disorders. Also, image studies provide evidence for a shared neurobiological basis, contributing to a dimensional diagnostic approach. This study aimed to identify the molecular mechanisms that differentiate SZ and BD patients from health controls but also that distinguish both from health individuals. Comparison of gene expression profiling in post-mortem brains of both disorders and health controls (30 cases), followed by a further comparison between 29 BD and 29 SZ revealed 28 differentially expressed genes. These genes were used in co-expression analysesthat revealed the pairs CCR1/SERPINA1, CCR5/HCST, C1QA/CD68, CCR5/S100A11 and SERPINA1/TLR1 as presenting the most significant difference in co-expression between SZ and BD. Next, a protein-protein interaction (PPI) network using the 28 differentially expressed genes as seeds revealed CASP4, TYROBP, CCR1, SERPINA1, CCR5 and C1QA as having a central role in the diseases manifestation. Both co-expression and network topological analyses pointed to genes related to microglia functions. Based on this data, we suggest that differences between SZ and BP are due to genes involved with response to stimulus, defense response, immune system process and response to stress biological processes, all having a role in the communication of environmental factors to the cells and associated to microglia. Copyright © 2014 Elsevier B.V. All rights reserved.
    Full-text · Article · Dec 2014 · Schizophrenia Research
  • Source
    • "Several susceptibility genes encoding for glutamate receptor subunits, including the Gria1 gene encoding for GluA1 subunit of AMPA-type glutamate receptor (previously named GLUA1, GluR1, GluRA, GluR-A [10]), have been identified for bipolar disease [11], [12]. Most of them are overlapping with schizophrenia [13], [14], as these two illnesses share many behavioural characteristics. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abnormal excitatory glutamate neurotransmission and plasticity have been implicated in schizophrenia and affective disorders. Gria1-/- mice lacking GluA1 subunit (encoded by Gria1 gene) of AMPA-type glutamate receptor show robust novelty-induced hyperactivity, social deficits and heightened approach features, suggesting that they could be used to test for anti-manic activity of drugs. Here, we tested the efficacy of chronic treatment with established anti-manic drugs on behavioural properties of the Gria1-/- mice. The mice received standard mood stabilizers (lithium and valproate) and novel ones (topiramate and lamotrigine, used more as anticonvulsants) as supplements in rodent chow for at least 4 weeks. All drugs attenuated novelty-induced locomotor hyperactivity of the Gria1-/- mice, especially by promoting the habituation, while none of them attenuated 2-mg/kg amphetamine-induced hyperactivity as compared to control diet. Treatment with lithium and valproate reversed the elevated exploratory activity of Gria1-/- mice. Valproate treatment also reduced struggling behaviour in tail suspension test and restored reciprocally-initiated social contacts of Gria1-/- mice to the level shown by the wild-type Gria1+/+ mice. Gria1-/- mice consumed slightly more sucrose during intermittent sucrose exposure than the wild-types, but ran similar distances on running wheels. These behaviours were not consistently affected by lithium and valproate in the Gria1-/- mice. The efficacy of various anti-manic drug treatments on novelty-induced hyperactivity suggests that the Gria1-/- mouse line can be utilized in screening for new therapeutics.
    Full-text · Article · Jun 2014 · PLoS ONE
Show more