Increased excitability of human iPSC-derived neurons in HTR2A variant-related sleep bruxism

Avijite Kumer Sarkar; Shiro Nakamura; Kento Nakai; Taro Sato; Takahiro Shiga; Yuka Abe; Yurie Hoashi; Tomio Inoue; Wado Akamatsu; Kazuyoshi Baba

doi:10.1016/j.scr.2022.102658

Increased excitability of human iPSC-derived neurons in HTR2A variant-related sleep bruxism

Stem Cell Res. 2022 Mar:59:102658. doi: 10.1016/j.scr.2022.102658. Epub 2022 Jan 3.

Authors

Avijite Kumer Sarkar¹, Shiro Nakamura², Kento Nakai³, Taro Sato⁴, Takahiro Shiga⁵, Yuka Abe⁶, Yurie Hoashi⁷, Tomio Inoue⁸, Wado Akamatsu⁹, Kazuyoshi Baba¹⁰

Affiliations

¹ Department of Prosthodontics, Showa University School of Dentistry, 2-1-1 Kitasenzoku, Ota-ku, Tokyo 145-8515, Japan. Electronic address: avijitesrk@dent.showa-u.ac.jp.
² Department of Oral Physiology, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. Electronic address: snaka@dent.showa-u.ac.jp.
³ Department of Prosthodontics, Showa University School of Dentistry, 2-1-1 Kitasenzoku, Ota-ku, Tokyo 145-8515, Japan. Electronic address: kentimo615@dent.showa-u.ac.jp.
⁴ Department of Prosthodontics, Showa University School of Dentistry, 2-1-1 Kitasenzoku, Ota-ku, Tokyo 145-8515, Japan. Electronic address: taro.s@dent.showa-u.ac.jp.
⁵ Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: t-shiga@juntendo.ac.jp.
⁶ Department of Prosthodontics, Showa University School of Dentistry, 2-1-1 Kitasenzoku, Ota-ku, Tokyo 145-8515, Japan. Electronic address: abeyuka@dent.showa-u.ac.jp.
⁷ Department of Prosthodontics, Showa University School of Dentistry, 2-1-1 Kitasenzoku, Ota-ku, Tokyo 145-8515, Japan. Electronic address: yuri-1020@dent.showa-u.ac.jp.
⁸ Department of Oral Physiology, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. Electronic address: inouet@dent.showa-u.ac.jp.
⁹ Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: awado@juntendo.ac.jp.
¹⁰ Department of Prosthodontics, Showa University School of Dentistry, 2-1-1 Kitasenzoku, Ota-ku, Tokyo 145-8515, Japan. Electronic address: kazuyoshi@dent.showa-u.ac.jp.

PMID: 34999422
DOI: 10.1016/j.scr.2022.102658

Abstract

Sleep bruxism (SB) is a sleep-related movement disorder characterized by grinding and clenching of the teeth during sleep. We previously found a significant association between SB and a single nucleotide polymorphism (SNP), rs6313, in the neuronal serotonin 2A receptor gene (HTR2A), and established human induced pluripotent stem cell (iPSC)-derived neurons from SB patients with a genetic variant. To elucidate the electrophysiological characteristics of SB iPSC-derived neural cells bearing an SB-related genetic variant, we generated ventral hindbrain neurons from SB patients and unaffected controls, and explored the intrinsic membrane properties of these neurons using the patch-clamp technique. We found that the electrophysiological properties of iPSC-derived neurons mature in a time-dependent manner in long-term control cultures. SB neurons exhibited higher action potential firing frequency, higher gain, and shorter action potential half duration. This is the first in vitro modeling of SB using patient-specific iPSCs. The revealed electrophysiological characteristics may serve as a benchmark for further investigation of pathogenic mechanisms underlying SB. Moreover, our results on long-term cultures provide a strategy to define the functional maturity of human neurons in vitro, which can be implemented for stem cell research of neurogenesis, and neurodevelopmental disorders.

Keywords: Altered excitability; Human induced pluripotent stem cells; Intrinsic membrane properties; Patch-clamp technique; Sleep bruxism; iPSC-derived neuronal maturation.