Increased excitability of human iPSC-derived neurons in HTR2A variant-related sleep bruxism
Increased excitability of human iPSC-derived neurons in HTR2A variant-related sleep bruxism
复制标题
HTR2A 变异相关的睡眠磨牙症中人类 iPSC 衍生神经元的兴奋性增加
DOI：
10.1016/j.scr.2022.102658
复制
发表时间：
2022
影响因子：
1.2
通讯作者：
Baba Kazuyoshi
中科院分区：
文献类型：
--
作者：
Sarkar Avijite Kumer;Nakamura Shiro;Nakai Kento;Sato Taro;Shiga Takahiro;Abe Yuka;Hoashi Yurie;Inoue Tomio;Akamatsu Wado;Baba Kazuyoshi
睡眠磨牙症（SB）是一种睡眠相关的运动障碍，其特征是在睡眠期间磨牙和咬牙。我们先前发现SB和神经元5-羟色胺2A受体基因（HTR 2A）中的单核苷酸多态性（SNP）rs6313之间存在显著关联，并从SB患者中建立了具有遗传变异的人类诱导多能干细胞（iPSC）衍生神经元。为了阐明SB iPSC衍生的神经细胞具有SB相关遗传变体的电生理学特征，我们从SB患者和未受影响的对照产生腹侧后脑神经元，并使用膜片钳技术探索这些神经元的固有膜特性。我们发现，iPSC衍生神经元的电生理特性在长期对照培养物中以时间依赖性方式成熟。SB神经元表现出较高的动作电位放电频率、较高的增益和较短的动作电位半时程。这是第一次使用患者特异性iPSC进行SB的体外建模。揭示的电生理特性可以作为一个基准，为进一步调查潜在的SB的致病机制。此外，我们的长期培养的结果提供了一个战略，以确定功能成熟的人神经元体外，这可以实施干细胞研究的神经发生，和神经发育障碍。
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 firstin vitromodeling 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 neuronsin vitro, which can be implemented for stem cell research of neurogenesis, and neurodevelopmental disorders.