TY - JOUR
T1 - A Key Role for Prefrontocortical Small Conductance Calcium-Activated Potassium Channels in Stress Adaptation and Rapid Antidepressant Response
AU - Bambico, Francis Rodriguez
AU - Li, Zhuoliang
AU - Creed, Meaghan
AU - De Gregorio, Danilo
AU - DIwan, Mustansir
AU - Li, Jessica
AU - McNeill, Sean
AU - Gobbi, Gabriella
AU - Raymond, Roger
AU - Nobrega, José N.
N1 - Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].
PY - 2020/3/14
Y1 - 2020/3/14
N2 - 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.
AB - 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.
KW - SK channel
KW - chronic unpredictable mild stress
KW - dorsal raphe nucleus
KW - muscarinic M receptor
KW - prelimbic cortex
UR - http://www.scopus.com/inward/record.url?scp=85083041469&partnerID=8YFLogxK
U2 - 10.1093/cercor/bhz187
DO - 10.1093/cercor/bhz187
M3 - Article
C2 - 31504265
AN - SCOPUS:85083041469
SN - 1047-3211
VL - 30
SP - 1559
EP - 1572
JO - Cerebral Cortex
JF - Cerebral Cortex
IS - 3
ER -