Antidepressant Activity of Pharmacological and Genetic Deactivation of the Small-Conductance Calcium-Activated Potassium Channel Subtype-3

Mina Nashed , Shannon Waye, SM Nageeb Hasan, Diana Nguyen, Micaela Wiseman, Jing Zhang, Harry Lau, O. Chandani Dinesh, Roger Raymond, Iain Greig, Francis Rodriguez Bambico* (Corresponding Author), Jose Nobrega

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale
The voltage-insensitive, small conductance calcium-activated potassium (SK) channel is a key regulator of neuronal depolarization, and is implicated in the pathophysiology of depressive disorders.
Objective
We ascertained whether the SK channel is impaired in the chronic unpredictable stress (CUS) model, and whether it can serve as a molecular target of antidepressant action.
Methods
We assessed the depressive-like behavioral phenotype of CUS-exposed rats, and
performed post-mortem SK channel binding and activity-dependent zif268 mRNA analyses on their brains. To begin an assessment of SK channel subtypes involved, we examined the effects of genetic and pharmacological inhibition of the SK3 channel using conditional knock-out mice and selective SK3 channel negative allosteric modulators (NAMs).
Results
We found that [ 125 I]apamin binding to SK channels is increased in the prefrontal cortex and decreased in the hippocampus, an effect that was associated with reciprocal levels of zif268 mRNA transcripts indicating abnormal regional cell activity in this model. We found that genetic and pharmacological manipulations significantly decreased immobility in the forced swim test without altering general locomotor activity, a hallmark of antidepressant-like activity.
Conclusions
Taken together, these findings link depression-related neural and behavioral
pathophysiology with abnormal SK channel functioning, and suggest that this can be reversed by the selective inhibition of SK3 channels.
Original languageEnglish
JournalPsychopharmacology
Publication statusAccepted/In press - 13 Dec 2021

Keywords

  • small-conductance calcium-activated potassium (SK) channel
  • antidepressant
  • chronic unpredictable mild stress
  • prefrontal cortex
  • SK3 NAM

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