Article

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

ABSTRACT

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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    • "Neuronal actin dynamics, i.e. the spatiotemporally controlled assembly and disassembly of actin filaments (F-actin), is an energy-costly process that may absorb up to 50% of the local available energy (Bernstein and Bamburg, 2003) and plays a critical role in different time-limited developmental stages including neuronal migration, neuritogenesis, synaptogenesis and synaptic plasticity (Bellenchi et al., 2007;Kullmann et al., 2012;Parisiadou et al., 2014;Rust et al., 2010;Schmidt et al., 2011). Disturbances in neuron migration and differentiation, or synapse maturation and physiology are among the most robust and key neurobiological findings that have been identified in mental disorders (Ben-David and Shifman, 2012;Brennand et al., 2012). Interestingly, some of the strongest candidate genes known to be involved in different mental disorders such as schizophrenia (DISC1, Shank2) or autism-spectrum disorders (Shank2, Shank3, FMRP) have recently been shown to specifically modulate neuronal actin dynamics (Duffney et al., 2013Duffney et al., , 2015Durand et al., 2012;Peykov et al., 2015;Reeve et al., 2005;Steinecke et al., 2014;Won et al., 2012). "

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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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