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Chunk #16 — Patient hiPscs-Derived Brain Cells for Modeling Schizophrenia — Modeling Regional Specificity and Circuitry

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Prospects for Modeling Abnormal Neuronal Function in Schizophrenia Using Human Induced Pluripotent Stem Cells.
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Although several protocols bias hiPSC differentiation into region-specific neurons, these methodologies fall far short of generating defined circuitry. Typically, hiPSCs are first transformed into neural progenitor cells (NPCs) through dual SMAD inhibition, which involves antagonism of bone morphogenic protein (BMP) and transforming growth factor beta (TGF-β) (Chambers et al., 2009). Such directed differentiation into NPCs (in contrast to allowing hiPSC colonies to differentiate in neural medium as in the studies by Brennand et al. (2011) and Pedrosa et al. (2011) significantly reduces variability in the subsequently derived neurons. The NPCs are then subjected to treatment with growth factors found in distinct regions of the developing brain. Thus, scientists have generated neurons specific to the medial and caudal ganglionic eminences (sites of GABAergic neuron development) (Ahn et al., 2016), cerebral cortex (Shi et al., 2012), and the dentate gyrus (Yu et al., 2014). Although directed-differentiation protocols are thought to more closely mimic in vivo development, the protracted timeline poses a major disadvantage. Viral-based induction strategies have been utilized to overexpress exogenous transcription factors to produce excitatory (Ho et al., 2016) and