GABA interneurons mediate the rapid antidepressant-like effects of scopolamine
Eric S. Wohleb, … , Meenakshi Alreja, Ronald S. Duman
Eric S. Wohleb, … , Meenakshi Alreja, Ronald S. Duman
Published June 6, 2016
Citation Information: J Clin Invest. 2016;126(7):2482-2494. https://doi.org/10.1172/JCI85033.
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Research Article Neuroscience

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

Abstract

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.

Authors

Eric S. Wohleb, Min Wu, Danielle M. Gerhard, Seth R. Taylor, Marina R. Picciotto, Meenakshi Alreja, Ronald S. Duman

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Figure 10

M1-AChR on SST interneurons mediates the rapid antidepressant response to scopolamine.

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M1-AChR on SST interneurons mediates the rapid antidepressant response t...
In the mPFC of WT mice, M1-AChR expression on SST-GABA interneurons is antagonized by scopolamine, leading to disinhibition of pyramidal glutamate (PYR-Glut) neurons, resulting in increased glutamate release. This causes activation of surrounding target pyramidal neurons and increased FosB expression. Importantly, this burst of glutamate also stimulates postsynaptic signaling pathways that increase synaptic number and function that ultimately underlie the rapid antidepressant actions of scopolamine. In the mPFC of Sst-Cre mice, M1-AChR knockdown on SST-GABA interneurons prevents scopolamine blockade of inhibitory input on pyramidal neurons. This lack of disinhibition or maintenance of GABA inhibition of PYR-Glut neurons prevents the glutamate burst and the downstream cellular and molecular pathways underlying the synaptic and antidepressant behavioral actions of scopolamine.