Neurobiological Perturbations in Bipolar Disorder Compared With Schizophrenia: Evidence From Cell Cultures and Brain Organoids

Abstract

Bipolar disorder (BD) and schizophrenia (SCZ) are uniquely human disorders with a complex pathophysiology that involves adverse neuropathological events in brain development. High disease polygenicity and limited access to live human brain tissue make these disorders exceedingly challenging to study mechanistically. Cellular cultures and brain organoids generated from human-derived pluripotent stem cells preserve the genetic background of the donor cells and recapitulate some of the defining characteristics of human brain architecture and early spatiotemporal development. These model systems have already proven successful in deciphering some of the neuropathological perturbations in BD and SCZ, and methodological advancements, such as the functional integration of 2 or more region-specific organoids and organoid transplantation in animals, promise to deliver increasingly refined insights. Here, we review a selection of recent discoveries achieved by stem cell-based models, with a particular focus on patterns of cellular and molecular convergence and divergence between BD and SCZ. First, we provide a brief overview of the evidence from glial and neuronal cell cultures and brain organoids, centering our discussion on several key functional domains, including neuroinflammation, neuronal excitability, and mitochondrial function. Then, we review recent findings demonstrating the power of integrating stem cell-based systems with gene editing technologies to elucidate the functional consequences of risk variants identified through genetic association studies. We end with a discussion of current challenges and some promising avenues for future research.

Keywords: Bipolar disorder; Genetic mapping; Neurodevelopment; Organoids; Schizophrenia; Stem cells.