GABA interneurons mediate the rapid antidepressant-like effects of scopolamine.
Major depressive disorder (MDD) is a recurring psychiatric illness that causes substantial health and socioeconomic burdens. Clinical reports have revealed that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in individuals with MDD. Preclinical models suggest that these rapid antidepressant effects can be recapitulated with blockade of M1-type muscarinic acetylcholine receptors (M1-AChR); however, the cellular mechanisms underlying activity-dependent synaptic and behavioral responses to scopolamine have not been determined. Here, we demonstrate that the antidepressant-like effects of scopolamine are mediated by GABA interneurons in the medial prefrontal cortex (mPFC). Both GABAergic (GAD67+) interneurons and glutamatergic (CaMKII+) interneurons in the mPFC expressed M1-AChR. In mice, viral-mediated knockdown of M1-AChR specifically in GABAergic neurons, but not glutamatergic neurons, in the mPFC attenuated the antidepressant-like effects of scopolamine. Immunohistology and electrophysiology showed that somatostatin (SST) interneurons in the mPFC express M1-AChR at higher levels than parvalbumin interneurons. Moreover, knockdown of M1-AChR in SST interneurons in the mPFC demonstrated that M1-AChR expression in these neurons is required for the rapid antidepressant-like effects of scopolamine. These data indicate that SST interneurons in the mPFC are a promising pharmacological target for developing rapid-acting antidepressant therapies.
Eric S
ES
Wohleb
Min
M
Wu
Danielle M
DM
Gerhard
Seth R
SR
Taylor
Marina R
MR
Picciotto
Meenakshi
M
Alreja
Ronald S
RS
Duman
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001007:Anxiety / Q000378:metabolism; D001522:Behavior, Animal; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017397:Prefrontal Cortex / Q000378:metabolism; D012601:Scopolamine / Q000494:pharmacology*
D000928:Antidepressive Agents; D012601:Scopolamine