HCN2 Channels in Cholinergic Interneurons of Nucleus Accumbens Shell Regulate Depressive Behaviors

Jia Cheng, Gali Umschweif, Jenny Leung, Yotam Sagi*, Paul Greengard

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


Cholinergic interneurons (ChIs) in the nucleus accumbens (NAc) have been implicated in drug addiction, reward, and mood disorders. However, the physiological role of ChIs in depression has not been characterized. Here, we show that the tonic firing rate of ChIs in NAc shell is reduced in chronic stress mouse models and in a genetic mouse model of depression. Chemogenetic inhibition of NAc ChIs renders naive mice susceptible to stress, whereas enhancement of ChI activity reverses depressive phenotypes. As a component of the molecular mechanism, we found that the expression and function of the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) are decreased in ChIs of NAc shell in depressed mice. Overexpression of HCN2 channels in ChIs enhances cell activity and is sufficient to rescue depressive phenotypes. These data suggest that enhancement of HCN2 channel activity in NAc ChIs is a feasible approach for the development of a new class of antidepressants. Cheng et al. show that decreased expression and function of HCN2 channels cause reduced ChI tonic activity in NAc shell that leads to depressive phenotypes. Targeting HCN2 channels to enhance ChI activity is sufficient to rescue depression.

Original languageAmerican English
Pages (from-to)662-672.e5
Issue number4
StatePublished - 20 Feb 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Inc.


  • BacTRAP
  • HCN2
  • MDD
  • cholinergic interneurons
  • mouse model of depression
  • nucleus accumbens
  • p11
  • shell and core
  • tonically active neurons


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