Induced pluripotent stem cells as tools to investigate the neurobiology of bipolar disorder and advance novel therapeutic discovery

Bipolar disorder presents one of the most challenging neuropsychiatric disorders to effectively treat and understand the underlying etiopathogenesis due to its complexity at multiple levels: clinical diagnosis, genetic architecture, and variable responsiveness to pharmacotherapy and other treatments. As a CNS disorder, gaining an understanding of the disease has been greatly hindered by the limited accessibility of human brain tissue and challenges to characterizing genetically accurate models. These limitations have meant the dissection of pathogenic mechanisms along with the discovery of disease-relevant biomarkers and novel therapeutic targets for bipolar disorder that has lagged behind other areas of medicine despite its prevalence and burden to individuals, families, and society as a whole. Increasingly though, human-induced pluripotent stem cell (hiPSC) technology provides an unprecedented opportunity to gain insight into the underling molecular and cellular pathology of a wide range of monogenic and polygenic CNS disorders, including bipolar disorder. Here, we will review this progress and the state of these efforts along with progress toward integrating hiPSC studies with studies in animal models and with human neuropathology that collectively hold potential to advance our understanding of the neurobiology of bipolar disorder and targeted therapeutics for its treatment and ideally prevention.