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M1 acetylcholine receptors in somatostatin interneurons contribute to GABAergic and glutamatergic plasticity in the mPFC and antidepressant-like responses

Neuropsychopharmacology volume 48, pages 1277–1287 (2023)Cite this article

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Abstract

Alterations in glutamatergic and GABAergic function in the medial prefrontal cortex (mPFC) are prevalent in individuals with major depressive disorder, resulting in impaired synaptic plasticity that compromises the integrity of signal transfer to limbic regions. Scopolamine, a non-selective muscarinic receptor antagonist, produces rapid antidepressant-like effects by targeting M1-type acetylcholine receptors (M1R) on somatostatin (SST) interneurons. So far, these effects have been investigated with relatively short-term manipulations, and long-lasting synaptic mechanisms involved in these responses are still unknown. Here, we generated mice with conditional deletion of M1R (M1f/fSstCre+) only in SST interneurons to determine the role of M1R in modulating long-term GABAergic and glutamatergic plasticity in the mPFC that leads to attenuation of stress-relevant behaviors. We have also investigated whether the molecular and antidepressant-like effects of scopolamine could be mimicked or occluded in male M1f/fSstCre+ mice. M1R deletion in SST-expressing neurons occluded the rapid and sustained antidepressant-like effects of scopolamine, as well as scopolamine-induced increases in c-Fos+/CaMKIIα cells and proteins necessary for glutamatergic and GABAergic function in the mPFC. Importantly, M1R SST deletion resulted in resilience to chronic unpredictable stress in behaviors relevant to coping strategies and motivation, and to a lesser extent, in behaviors relevant to avoidance. Finally, M1R SST deletion also prevented stress-induced impairments in the expression of GABAergic and glutamatergic markers in the mPFC. These findings suggest that the antidepressant-like effects of scopolamine result from modulation of excitatory and inhibitory plasticity via M1R blockade in SST interneurons. This mechanism could represent a promising strategy for antidepressant development.

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Fig. 1: Selective genetic deletion of M1R in somatostatin interneurons.
Fig. 2: M1R deletion in SST interneurons blocks the rapid and sustained antidepressant- and anxiolytic-like effects of scopolamine.
Fig. 3: M1R deletion in SST interneurons prevents scopolamine-induced increase in GABAergic and glutamatergic protein levels in the mPFC.
Fig. 4: M1R deletion in SST interneurons prevents scopolamine-induced increase in c-Fos expression in CaMKIIα (glutamatergic) neurons in the mPFC.
Fig. 5: M1R deletion in SST interneurons promotes stress resilience and prevents glutamate- and GABA-related protein deficits in the mPFC of M1f/fSstCre+ mice.

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Acknowledgements

RSD passed away on February 1, 2020. This article is dedicated to RSD in memory of his great mentorship and scientific leadership.

Funding

This study was supported by grant K99MH126098, MH077681, MH105910 and NARSAD Young Investigator Award 2020 (BBRF Foundation, #29063). This work was funded in part by the State of Connecticut, Department of Mental Health and Addiction Services, but this publication does not express the views of the Department of Mental Health and Addiction Services or the State of Connecticut.

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  1. Deceased: Ronald S. Duman.

Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT, 06519, USA

    Manoela V. Fogaça, Min Wu, Chan Li, Xiao-Yuan Li, Ronald S. Duman & Marina R. Picciotto

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  1. Manoela V. Fogaça
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  2. Min Wu
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Contributions

MVF designed the study, performed the experiments, analyzed the data and wrote the manuscript. MW performed the electrophysiological experiments and analyzed the data. X-YL and CL provided technical support and helped to perform the experiments. RSD contributed to experimental design and was involved in data interpretation and analyses. MRP provided scientific input, was involved in data interpretation and analyses, edited and revised the manuscript.

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Correspondence to Manoela V. Fogaça.

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Fogaça, M.V., Wu, M., Li, C. et al. M1 acetylcholine receptors in somatostatin interneurons contribute to GABAergic and glutamatergic plasticity in the mPFC and antidepressant-like responses. Neuropsychopharmacol. 48, 1277–1287 (2023). https://doi.org/10.1038/s41386-023-01583-7

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