TMEM16A expression in cholinergic neurons of the medial habenula mediates anxiety-related behaviors

Chang Hoon Cho, Sangjoon Lee, Ajung Kim, Oleg Yarishkin, Kanghyun Ryoo, Young Sun Lee, Hyun Gug Jung, Esther Yang, Da Yong Lee, Byeongjun Lee, Hyun Kim, Uhtaek Oh, Heh In Im, Eun Mi Hwang, Jae Yong Park

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


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.

Original languageEnglish
Article numbere48097
JournalEMBO Reports
Issue number2
Publication statusPublished - 2020 Feb 5

Bibliographical note

Publisher Copyright:
© 2019 The Authors


  • TMEM16A
  • anxiety
  • cholinergic neurons
  • medial habenula
  • social interaction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics


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