Modeling psychiatric disorders at the cellular and network levels

Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA.
Molecular Psychiatry (Impact Factor: 14.5). 04/2012; 17(12). DOI: 10.1038/mp.2012.20
Source: PubMed


Although psychiatric disorders such as autism spectrum disorders, schizophrenia and bipolar disorder affect a number of brain regions and produce a complex array of clinical symptoms, basic phenotypes likely exist at the level of single neurons and simple networks. Being highly heritable, it is hypothesized that these disorders are amenable to cell-based studies in vitro. Using induced pluripotent stem cell-derived neurons and/or induced neurons from fibroblasts, limitless numbers of live human neurons can now be generated from patients with a genetic background permissive to the disease state. We predict that cell-based studies will ultimately contribute to our understanding of the initiation, progression and treatment of these psychiatric disorders.Molecular Psychiatry advance online publication, 3 April 2012; doi:10.1038/mp.2012.20.

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Available from: Kristen Brennand, Oct 07, 2014
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    • "Once these abnormalities are clearly defined, iPSCs or iNEURONS can then be tested for responsiveness to specific psychoactive drugs. As an example, iPSCderived neurons obtained from fibroblasts of patients with schizophrenia display decreased neurite number, reduced neuronal connectivity, and abnormal gene expression related to glutamate receptors, cytoskeletal remodelling and oxidative stress; at least some of these parameters respond to antipsychotic treatment (Brennand et al., 2012). Several experimental paradigms involving iPSC or iNEURON models of neurodevelopmental disorders have been published to date, underscoring the heuristic potential of this approach (Krey et al., 2013; Cocks et al., 2014; Doers et al., 2014). "
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    • "Although psychiatric disorders, such as schizophrenia, affect several brain regions and produce a complex array of clinical symptoms, basic phenotypes likely exist at the level of single neurons and simple networks. Being highly heritable, it is hypothesized that these disorders are amenable to cell-based studies in vitro (Brennand et al., 2012). Accordingly, the human-induced PSC (hiPSC) technology makes it possible to study schizophrenia and other psychiatric disorders using live human neurons with a genetic predisposition without knowledge of the genes interacting to produce the disease state. "
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    • "Given the lack of alternative sources, a major effort has been directed toward the development of differentiation protocols that convert pluripotent stem cells into neurons to allow examination of healthy human neurons and of neurons derived from patients with a variety of neurological diseases. In this approach, fibroblasts from patients with poorly understood diseases—such as schizophrenia or Alzheimer's disease—are converted into iPSCs that are then differentiated into neurons to study the pathogenesis of these diseases (reviewed in Han et al., 2011; Ming et al., 2011; Brennand et al., 2012; Marchetto and Gage 2012). Moreover, elegant studies have described differentiation protocols that produce distinct types of neurons in vitro, although the number and properties of different types of human neurons in situ are largely unknown and are only now beginning to be defined. "
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