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

Author:

Yamamoto Kana,Kuriu ToshihikoORCID,Matsumura Kensuke,Nagayasu Kazuki,Tsurusaki Yoshinori,Miyake Noriko,Yamamori Hidenaga,Yasuda Yuka,Fujimoto Michiko,Fujiwara Mikiya,Baba Masayuki,Kitagawa Kohei,Takemoto Tomoya,Gotoda-Nishimura Nanaka,Takada Tomohiro,Seiriki Kaoru,Hayata-Takano Atsuko,Kasai AtsushiORCID,Ago YukioORCID,Kida SatoshiORCID,Takuma Kazuhiro,Ono FumihitoORCID,Matsumoto NaomichiORCID,Hashimoto Ryota,Hashimoto HitoshiORCID,Nakazawa TakanobuORCID

Abstract

AbstractAn 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.

Funder

MEXT | Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

Takeda Science Foundation

Asahi Glass Foundation

Naito Foundation

Publisher

Springer Science and Business Media LLC

Subject

Biological Psychiatry,Cellular and Molecular Neuroscience,Psychiatry and Mental health

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