Multiple alterations in glutamatergic transmission and dopamine D2 receptor splicing in induced pluripotent stem cell-derived neurons from patients with familial schizophrenia

作者：Kana Yamamoto, Toshihiko Kuriu, Kensuke Matsumura, Kazuki Nagayasu, Yoshinori Tsurusaki, Noriko Miyake, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Mikiya Fujiwara, Masayuki Baba, Kohei Kitagawa, Tomoya Takemoto, Nanaka Gotoda-Nishimura, T. Takada, Kaoru Seiriki, Atsuko Hayata‐Takano, Atsushi Kasai, Yukio Ago, Satoshi Kida, Kazuhiro Takuma, Fumihito Ono, Naomichi Matsumoto, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa · 发表于：Translational Psychiatry · 年份：2021 · DOI：10.1038/s41398-021-01676-1 · 被引用次数：17 · 研究领域：Pluripotent Stem Cells Research、CRISPR and Genetic Engineering、Single-cell and spatial transcriptomics

An increasing body of evidence suggests that impaired synapse development and function are associated with schizophrenia; however, the underlying molecular pathophysiological mechanism of the disease remains largely unclear. We conducted a family-based study combined with molecular and cellular analysis using induced pluripotent stem cell (iPSC) technology. We generated iPSCs from patients with familial schizophrenia, differentiated these cells into neurons, and investigated the molecular and cellular phenotypes of the patient's neurons. We identified multiple altered synaptic functions, including increased glutamatergic synaptic transmission, higher synaptic density, and altered splicing of dopamine D2 receptor mRNA in iPSC-derived neurons from patients. We also identified patients' specific genetic mutations using whole-exome sequencing. Our findings support the notion that altered synaptic function may underlie the molecular and cellular pathophysiology of schizophrenia, and that multiple genetic factors cooperatively contribute to the development of schizophrenia.