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Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses

Molecular Psychiatry volume 26, pages 3277–3291 (2021)Cite this article

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Abstract

Major depressive disorder (MDD) is associated with alterations of GABAergic interneurons, notably somatostatin (Sst) as well as parvalbumin (Pvalb), in cortical brain areas. In addition, the antidepressant effects of rapid-acting drugs are thought to occur via inhibition of GABA interneurons. However, the impact of these interneuron subtypes in affective behaviors as well as in the effects of rapid-acting antidepressants remains to be determined. Here, we used a Cre-dependent DREADD-chemogenetic approach to determine if inhibition of GABA interneurons in the mPFC of male mice is sufficient to produce antidepressant actions, and conversely if activation of these interneurons blocks the rapid and sustained antidepressant effects of scopolamine, a nonselective acetylcholine muscarinic receptor antagonist. Chemogenetic inhibition of all GABA interneurons (Gad1+), as well as Sst+ and Pvalb+ subtypes in the mPFC produced dose and time-dependent antidepressant effects in the forced swim and novelty suppressed feeding tests, and increased synaptic plasticity. In contrast, stimulation of Gad1, Sst, or Pvalb interneurons in mPFC abolished the effects of scopolamine and prevented scopolamine induction of synaptic plasticity. The results demonstrate that transient inhibition of GABA interneurons promotes synaptic plasticity that underlies rapid antidepressant responses.

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Fig. 1: Chemogenetic activation of Gad1 interneurons in the mPFC produces time- and dosing-dependent rapid antidepressant-like effects.
Fig. 2: Chemogenetic inhibition of Sst or Pvalb interneurons in the mPFC produces fast antidepressant-like effects and increases c-Fos expression.
Fig. 3: Chemogenetic inhibition of Sst or Pvalb interneurons in the mPFC increases VGLUT1 expression.
Fig. 4: Chemogenetic activation of Gad1, Pvalb, or Sst interneurons in the mPFC abolishes the rapid antidepressant-like effects of scopolamine.
Fig. 5: Chemogenetic activation of Sst or Pvalb interneurons abolishes scopolamine induction of VGLUT1 in the mPFC.

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Acknowledgements

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

Funding

This study was supported by a grant from MH093897 and MH105910. RSD has received consulting, speaking fees, and/or grant support from Psychogenics, Aptynx, Taisho, Johnson & Johnson, Lilly, Lundbeck, Relmada, Sumitomo Dianippon, Navitor, and Allergan.

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  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, Marina R. Picciotto & Ronald S. Duman

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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 performed the genotyping of the animals. CL helped to perform the CUS experiments. MRP provided scientific input for experiments added in revision and contributed to editing and revising the manuscript. RSD designed the study, revised, and contributed to writing the manuscript.

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Correspondence to Manoela V. Fogaça.

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Fogaça, M.V., Wu, M., Li, C. et al. Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses. Mol Psychiatry 26, 3277–3291 (2021). https://doi.org/10.1038/s41380-020-00916-y

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