As a proof-of-principle, several recent studies have now shown that hiPSC-derived neurons from patients with psychiatric disorders exhibit significant aberrations in neuronal connectivity, synapse maturation, and synaptic function compared with those of healthy controls (Brennand et al., 2011; Cheung et al., 2011; Marchetto et al., 2010; Pasca et al., 2011). Brennand et al (2011) studied hiPSC-derived neurons from four schizophrenia patients with unknown disease etiologies. Schizophrenia-hiPSC-derived neurons had significantly reduced neuronal connectivity, reduced neurite outgrowth, reduced dendritic levels of PSD95, and altered gene expression profiles. Defects in neuronal connectivity and gene expression were ameliorated following treatment with the dopamine receptor antagonist loxapine. These early studies provide clues into the neurobiological processes that underlie schizophrenia, but without information on the genetic contributors in these patients, a clear mechanistic understanding is lacking.
