Mina G Nashed1, Shannon Waye2, S M Nageeb Hasan2, Diana Nguyen1, Micaela Wiseman1, Jing Zhang1, Harry Lau1, O Chandani Dinesh2, Roger Raymond1, Iain R Greig3, Francis Rodriguez Bambico4,5, José N Nobrega1. 1. Behavioural Neurobiology Laboratory, Research Imaging Center, Centre for Addiction and Mental Health (CAMH), Toronto, ON, M5T 1R8, Canada. 2. Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland & Labrador, A1B 3X9, Canada. 3. Institute of Medical Sciences, University of Aberdeen, King's College, Aberdeen, AB25 2ZD, Scotland. 4. Behavioural Neurobiology Laboratory, Research Imaging Center, Centre for Addiction and Mental Health (CAMH), Toronto, ON, M5T 1R8, Canada. fbambico@mun.ca. 5. Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland & Labrador, A1B 3X9, Canada. fbambico@mun.ca.
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 knockout mice and selective SK3 channel negative allosteric modulators (NAMs). RESULTS: We found that [125I]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.
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 knockout mice and selective SK3 channel negative allosteric modulators (NAMs). RESULTS: We found that [125I]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.
Authors: Francis Rodriguez Bambico; Zhuoliang Li; Caio Oliveira; Sean McNeill; Mustansir Diwan; Roger Raymond; José N Nobrega Journal: Psychopharmacology (Berl) Date: 2019-02-22 Impact factor: 4.530
Authors: J L Cadet; C Brannock; I N Krasnova; S Jayanthi; B Ladenheim; M T McCoy; D Walther; A Godino; M Pirooznia; R S Lee Journal: Mol Psychiatry Date: 2016-04-05 Impact factor: 15.992