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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

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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 1

M1-AChR colocalized with CaMKII+ and GAD67+ neurons in the mPFC.

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M1-AChR colocalized with CaMKII+ and GAD67+ neurons in the mPFC.
WT mice...
WT mice were perfused, and brains were processed for immunohistology. Representative confocal images of immunofluorescent labeling in the mPFC are shown. (A) Images of CaMKII (green) and M1-AChR (red) in the mPFC are shown. Original magnification, ×40. Scale bar: 100 μm. (B) Magnified images of the dashed portion are shown. Original magnification, ×40, zoom 3. Scale bar: 25 μm. (C) Subsequent sections labeled with GAD67 (green) and M1-AChR (red) are shown. Original magnification, ×40, zoom 3. Scale bar: 25 μm. Arrows show neurons colabeled for specific marker and M1-AChR, while arrowheads show neurons that only label with M1-AChR.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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