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TMEM16A expression in cholinergic neurons of the medial habenula mediates anxiety-related behaviors.
EMBO Reports ( IF 7.7 ) Pub Date : 2019-11-29 , DOI: 10.15252/embr.201948097
Chang-Hoon Cho 1 , Sangjoon Lee 2, 3, 4 , Ajung Kim 5, 6 , Oleg Yarishkin 5 , Kanghyun Ryoo 1 , Young-Sun Lee 1 , Hyun-Gug Jung 1, 5 , Esther Yang 7 , Da Yong Lee 5 , Byeongjun Lee 8 , Hyun Kim 7 , Uhtaek Oh 8 , Heh-In Im 2, 4, 9 , Eun Mi Hwang 5, 6, 9 , Jae-Yong Park 1
Affiliation  

TMEM16A, a Ca2+ -activated Cl- channel, is known to modulate the excitability of various types of cells; however, its function in central neurons is largely unknown. Here, we show the specific expression of TMEM16A in the medial habenula (mHb) via RNAscope in situ hybridization, immunohistochemistry, and electrophysiology. When TMEM16A is ablated in the mHb cholinergic neurons (TMEM16A cKO mice), the slope of after-hyperpolarization of spontaneous action potentials decreases and the firing frequency is reduced. Reduced mHb activity also decreases the activity of the interpeduncular nucleus (IPN). Moreover, TMEM16A cKO mice display anxiogenic behaviors and deficits in social interaction without despair-like phenotypes or cognitive dysfunctions. Finally, chemogenetic inhibition of mHb cholinergic neurons using the DREADD (Designer Receptors Exclusively Activated by Designer Drugs) approach reveals similar behavioral phenotypes to those of TMEM16A cKO mice. We conclude that TMEM16A plays a key role in anxiety-related behaviors regulated by mHb cholinergic neurons and could be a potential therapeutic target against anxiety-related disorders.

中文翻译:

内侧缰核胆碱能神经元中的 TMEM16A 表达介导焦虑相关行为。

TMEM16A 是一种 Ca2+ 激活的 Cl- 通道,已知可以调节各种类型细胞的兴奋性;然而,其在中枢神经元中的功能很大程度上未知。在这里,我们通过 RNAscope 原位杂交、免疫组织化学和电生理学显示了 TMEM16A 在内侧缰核 (mHb) 中的特异性表达。当 mHb 胆碱能神经元(TMEM16A cKO 小鼠)中 TMEM16A 被消除时,自发动作电位后超极化的斜率降低,放电频率降低。mHb 活性降低也会降低脚间核 (IPN) 的活性。此外,TMEM16A cKO 小鼠表现出焦虑行为和社交互动缺陷,但没有类似绝望的表型或认知功能障碍。最后,使用 DREADD(由设计药物独家激活的设计受体)方法对 mHb 胆碱能神经元进行化学遗传学抑制,揭示了与 TMEM16A cKO 小鼠相似的行为表型。我们得出的结论是,TMEM16A 在 mHb 胆碱能神经元调节的焦虑相关行为中发挥着关键作用,并且可能成为对抗焦虑相关疾病的潜在治疗靶点。
更新日期:2020-02-06
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