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

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. Synopsis: The TMEM16A chloride channel has an excitatory role in cholinergic neurons of the medial habenula (mHb). Mice deficient for TMEM16A in mHb cholinergic neurons display anxiety‐related behaviors. TMEM16A is expressed in the medial habenula (mHb), and reduced activity of the mHb due to TMEM16A ablation reduces activity of the interpeduncular nucleus.Mice deficient for TMEM16A in mHb cholinergic neurons and mice with reduced activity of mHb neurons due to chemogenetic inhibition display anxiogenic behaviors and social interaction deficits.TMEM16A might be a potential therapeutic target against anxiety‐related disorders. [ABSTRACT FROM AUTHOR]