A Key Role for Prefrontocortical Small Conductance Calcium-Activated Potassium Channels in Stress Adaptation and Rapid Antidepressant Response

Francis Rodriguez Bambico, Zhuoliang Li, Meaghan Creed, Danilo De Gregorio, Mustansir DIwan, Jessica Li, Sean McNeill, Gabriella Gobbi, Roger Raymond, José N. Nobrega

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The muscarinic acetylcholine receptor antagonist scopolamine elicits rapid antidepressant activity, but its underlying mechanism is not fully understood. In a chronic stress model, a single low-dose administration of scopolamine reversed depressive-like reactivity. This antidepressant-like effect was mediated via a muscarinic M1 receptor-SKC pathway because it was mimicked by intra-medial prefrontal cortex (intra-mPFC) infusions of scopolamine, of the M1 antagonist pirenzepine or of the SKC antagonist apamin, but not by the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine. Extracellular and whole-cell recordings revealed that scopolamine and ketamine attenuate the SKC-mediated action potential hyperpolarization current and rapidly enhance mPFC neuronal excitability within the therapeutically relevant time window. The SKC agonist 1-EBIO abrogated scopolamine-induced antidepressant activity at a dose that completely suppressed burst firing activity. Scopolamine also induced a slow-onset activation of raphe serotonergic neurons, which in turn was dependent on mPFC-induced neuroplasticity or excitatory input, since mPFC transection abolished this effect. These early behavioral and mPFC activational effects of scopolamine did not appear to depend on prefrontocortical brain-derived neurotrophic factor and serotonin-1A activity, classically linked to SSRIs, and suggest a novel mechanism associated with antidepressant response onset through SKC-mediated regulation of activity-dependent plasticity.

Original languageEnglish
Pages (from-to)1559-1572
Number of pages14
JournalCerebral Cortex
Volume30
Issue number3
DOIs
StatePublished - Mar 14 2020

Keywords

  • SK channel
  • chronic unpredictable mild stress
  • dorsal raphe nucleus
  • muscarinic M receptor
  • prelimbic cortex

Fingerprint

Dive into the research topics of 'A Key Role for Prefrontocortical Small Conductance Calcium-Activated Potassium Channels in Stress Adaptation and Rapid Antidepressant Response'. Together they form a unique fingerprint.

Cite this