Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels

Elife. 2016 Nov 22:5:e21416. doi: 10.7554/eLife.21416.


The activity of serotonin (5-HT) neurons is critical for mood regulation. In a mouse model of chronic social isolation, a known risk factor for depressive illness, we show that 5-HT neurons in the dorsal raphe nucleus are less responsive to stimulation. Probing the responsible cellular mechanisms pinpoints a disturbance in the expression and function of small-conductance Ca2+-activated K+ (SK) channels and reveals an important role for both SK2 and SK3 channels in normal regulation of 5-HT neuronal excitability. Chronic social isolation renders 5-HT neurons insensitive to SK2 blockade, however inhibition of the upregulated SK3 channels restores normal excitability. In vivo, we demonstrate that inhibiting SK channels normalizes chronic social isolation-induced anxiety/depressive-like behaviors. Our experiments reveal a causal link for the first time between SK channel dysregulation and 5-HT neuron activity in a lifelong stress paradigm, suggesting these channels as targets for the development of novel therapies for mood disorders.

Keywords: SK3; calcium-activated potassium channels; depressive-like behaviors; dorsal raphe; mouse; neuroscience; serotonin neurons; social isolation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Evoked Potentials
  • Mice
  • Models, Animal
  • Neurons / physiology*
  • Serotonin / metabolism*
  • Serotonin Receptor Agonists / metabolism*
  • Small-Conductance Calcium-Activated Potassium Channels / metabolism*
  • Social Isolation*


  • Kcnn2 protein, mouse
  • Kcnn3 protein, mouse
  • Serotonin Receptor Agonists
  • Small-Conductance Calcium-Activated Potassium Channels
  • Serotonin

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.