title: Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels.
abstract: 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.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Derya
authors.identifier: 0000-0002-0253-5442
authors.initials: D
authors.lastname: Sargin
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: David K
authors.identifier: 0000-0003-1210-8409
authors.initials: DK
authors.lastname: Oliver
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.|Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada.|Department of Psychiatry, University of Toronto, Toronto, Canada.
authors.forename: Evelyn K
authors.identifier: 0000-0002-5994-6090
authors.initials: EK
authors.lastname: Lambe
mesh_terms: D000818:Animals; D005071:Evoked Potentials; D051379:Mice; D023421:Models, Animal; D009474:Neurons / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D012934:Social Isolation
chemical_list: C496898:Kcnn2 protein, mouse; C496900:Kcnn3 protein, mouse; D017366:Serotonin Receptor Agonists; D051640:Small-Conductance Calcium-Activated Potassium Channels; D012701:Serotonin
keywords: SK3; calcium-activated potassium channels; depressive-like behaviors; dorsal raphe; mouse; neuroscience; serotonin neurons; social isolation