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

• Published in: Stem cell research Vol. 59; p. 102658
• Main Authors: Sarkar, Avijite Kumer, Nakamura, Shiro, Nakai, Kento, Sato, Taro, Shiga, Takahiro, Abe, Yuka, Hoashi, Yurie, Inoue, Tomio, Akamatsu, Wado, Baba, Kazuyoshi
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 01.03.2022; Elsevier
• Subjects: Altered excitability; Human induced pluripotent stem cells; Intrinsic membrane properties; iPSC-derived neuronal maturation; Patch-clamp technique; Sleep bruxism; Intrinsic membrane properties; Cm; HTR2A; Sleep bruxism; SB; DMEM; Shh; SNP; Human induced pluripotent stem cells; TGF-β; Rm; BDNF; iPSC; Altered excitability; τm; Patch-clamp technique; 5-HT2AR; RA; AP; DIV; FGF-2; GDNF; RMP; iPSC-derived neuronal maturation; SEM; PM; GAPDH
• ISSN: 1873-5061; 1876-7753
• DOI: 10.1016/j.scr.2022.102658

[Display omitted] •Electrophysiological properties of human iPSC-derived neurons mature over time.•A strategy to define the functional maturity of human neurons in vitro.•Sleep bruxism (SB) neurons exhibited higher action potential firing frequency.•SB neurons displayed shorter action potential half duration.•The first human iPSC-derived neuronal model to study sleep bruxism. 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.