hiPSC Models Relevant to Schizophrenia

Probing the etiology of schizophrenia currently relies upon brain imaging, postmortem, and animal studies, although a wealth of information has been garnered using such methodologies, there are limitations. Brain imaging studies reveal information about brain volume and structural changes at the gross level only; postmortem studies uncover the state of the brain at disease endpoint, but are confounded by environmental factors such as patient treatment history, poverty, drug and alcohol abuse; animal studies rely on a priori knowledge of the genomic loci contributing to disease, and so typically model only single highly penetrant risk alleles (such as DISC1 or NRG1). The derivation of induced pluripotent stem cells from schizophrenia patients allows investigators to capture the full complement of genetic insults (known and unknown) that contribute to disease onset or progression. With more efficient derivation of functional and defined neuronal populations from patient cells, investigators can overcome the lack of live human brain tissue for study, enabling the unraveling of the specific cellular phenotypes and molecular mechanisms underlying schizophrenia. Moreover, combining the amenability of pluripotent stem cells to genetic manipulation, with in-depth analysis through transcriptome sequencing, will, for the first time, facilitate hypothesis testing of putative causal gene or regulatory networks involved in disease initiation or progression. The following chapter reviews the advancements in the application of induced pluripotent stem cells to the in vitro modeling of schizophrenia.