Editors' ChoiceDepression

Targeting pacemaker channels in depression

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Science Translational Medicine  30 Jan 2019:
Vol. 11, Issue 477, eaaw5318
DOI: 10.1126/scitranslmed.aaw5318


Hyperpolarization-activated cyclic nucleotide–gated channel dysfunction drives stress susceptibility and depression-like behavior.

Conventional antidepressant drugs target serotonin and other monoamine signaling molecules to relieve depressive symptoms over a period of weeks to months, but they are not always effective. In addition, they also act nonspecifically throughout the brain and body, causing a variety of side effects that limit their usefulness in many patients. Now, Cheng et al. show that hyperpolarization-activated cyclic nucleotide–gated (HCN) ion channels—a highly specific potential therapeutic target—play a critical role in controlling stress resilience and driving depression-like behavior in mice.

HCN channels are important molecular pacemakers that regulate cardiac rhythmicity and communication between neurons, and their malfunction is thus thought to play a role in cardiac arrhythmias, epilepsy, neuropathic pain, and other diseases. Although they have been implicated in depression-related behavior in mice, the underlying mechanisms remain incompletely understood. Cheng et al. found that the cholinergic interneurons (ChIs) in the nucleus accumbens are hypoactive in genetic and chronic stress mouse models. Suppressing the activity of this cell population using a chemogenetic approach rendered mice more susceptible to mild stressors and disrupted social interaction, reward-seeking, and other behaviors. Conversely, enhancing their activity was sufficient to reverse the effects of stress on behavior, but only after two weeks of treatment. To identify potential treatment targets, the authors performed transcriptomic analyses of RNA isolated from ChIs in the nucleus accumbens. They found that a specific HCN isoform—HCN2—was consistently underexpressed in all three mouse models tested. Selectively overexpressing HCN2 in the nucleus accumbens ChIs rescued their activity deficits and elicited antidepressant-like effects on behavior within three days. Future studies will be required to evaluate the extent to which similar mechanisms are involved in humans. Still, these exciting results suggest that pharmacological agents targeting HCN2 channels and related signaling molecules in this highly specific cell type in the nucleus accumbens might achieve relatively rapid antidepressant effects while minimizing side effects.

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