Application of induced pluripotent stem cells to understand neurobiological basis of bipolar disorder and schizophrenia

Abstract

The etiology of neuropsychiatric disorders, such as schizophrenia and bipolar disorder, usually involves complex combinations of genetic defects/variations and environmental impacts, which hindered, for a long time, research efforts based on animal models and patients' non-neuronal cells or post-mortem tissues. However, the development of human induced pluripotent stem cell (iPSC) technology by the Yamanaka group was immediately applied to establish cell research models for neuronal disorders. Since then, techniques to achieve highly efficient differentiation of different types of neural cells following iPSC modeling have made much progress. The fast-growing iPSC and neural differentiation techniques have brought valuable insights into the pathology and neurobiology of neuropsychiatric disorders. In this article, we first review the application of iPSC technology in modeling neuronal disorders and discuss the progress in the accompanying neural differentiation. Then, we summarize the progress in iPSC-based research that has been accomplished so far regarding schizophrenia and bipolar disorder.

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

“…In studies using iPSC‐derived neurons derived from BD patients, increased expression of genes involved in ventralization, decreased WNT signaling, and altered expression of genes involved in RNA metabolism were reported . In a study in which hippocampal dentate gyrus granule cells prepared from iPSC of six BD patients (three lithium responders and three non‐responders) were analyzed, patients’ neurons were found to have changes in mitochondrial function, such as increased mitochondrial membrane potential, decreased mitochondrial size, and increased expression of mtDNA‐derived transcripts.…”

Developmental excitation-inhibition imbalance underlying psychoses revealed by single-cell analyses of discordant twins-derived cerebral organoids

“…Mounting research using patient-derived iPSCs has proposed several cellular pathways altered in these psychiatric disorders, including synaptic function and Wnt signaling [ 8 ]. However, most of these studies differentiated the iPSCs into a predefined specific cell type.…”

Making psychiatry a clinical neuroscience‐based medicine

“…Recent genome‐wide association studies have shown the utility of polygenic risk scores (PRS), and analyses using PRS have confirmed traditional clinical findings, for example, early age at onset in major depression as a risk factor of bipolar disorder . Moreover, development of induced pluripotent cell technology has enabled the analysis of patients’ neurons in vitro for the first time …”

“…However, such remarkable progress has not yet caused innovation in clinical practice in psychiatry, and daily practice in clinics is mostly similar to that of several decades ago. Paradoxically, the progress of biological research has obscured the boundary of diagnostic categories: The same classes of drugs are effective for different types of diseases and there is an overlap in genetic, neuroimaging, and cellular findings across different mental disorders . This may indicate that current biological studies in psychiatry have not grown out of understanding mental disorders’ symptomatic‐level phenomena.…”