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Parvalbumin interneuron mGlu5 receptors govern sex differences in prefrontal cortex physiology and binge drinking

Neuropsychopharmacology (2024)Cite this article

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Abstract

Despite established sex differences in the prevalence and presentation of psychiatric disorders, little is known about the cellular and synaptic mechanisms that guide these differences under basal conditions. The proper function of the prefrontal cortex (PFC) is essential for the top-down regulation of motivated behaviors. The activity of the PFC is tightly controlled by parvalbumin-expressing interneurons (PV-INs), a key subpopulation of fast-spiking GABAergic cells that regulate cortical excitability through direct innervations onto the perisomatic regions of nearby pyramidal cells. Recent rodent studies have identified notable sex differences in PV-IN activity and adaptations to experiences such as binge drinking. Here, we investigated the cellular and molecular mechanisms that underlie sex-specific regulation of PFC PV-IN function. Using whole-cell patch-clamp electrophysiology and selective pharmacology, we report that PV-INs from female mice are more excitable than those from males. Moreover, we find that mGlu1 and mGlu5 metabotropic glutamate receptors regulate cell excitability, excitatory drive, and endocannabinoid signaling at PFC PV-INs in a sex-dependent manner. Genetic deletion of mGlu5 receptors from PV-expressing cells abrogates all sex differences observed in PV-IN membrane and synaptic physiology. Lastly, we report that female, but not male, PV-mGlu5−/− mice exhibit decreased voluntary drinking on an intermittent access schedule, which could be related to changes in ethanol’s stimulant properties. Importantly, these studies identify mGlu1 and mGlu5 receptors as candidate signaling molecules involved in sex differences in PV-IN activity and behaviors relevant to alcohol use.

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Fig. 1: PV-INs from female mice are more excitable at baseline, and PV-INs from male mice are more responsive to mGlu1/5 receptor stimulation.
Fig. 2: mGlu1 and mGlu5 receptors sex-specifically regulate synaptic strength and endocannabinoid plasticity in PV-Ins.
Fig. 3: Cell type-specific genetic deletion of Grm5 abrogates sex differences in PV-IN membrane physiology.
Fig. 4: Cell-type specific genetic deletion of Grm5 abrogates sex differences in PV-IN synaptic physiology.
Fig. 5: Female but not male PV-mGlu5−/− mice display reduced binge drinking.

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Acknowledgements

We thank members of the University of Pittsburgh Department of Psychiatry and Translational Neuroscience Program for stimulating discussions.

Funding

This work was supported by the National Institutes of Health [grant numbers R00AA027806 and R01MH120066], the Whitehall Foundation [grant number 2022-08-005], and the Brain and Behavior Research Foundation. CBF and RHC were supported by the Center for Neuroscience at the University of Pittsburgh. CBF was supported by an institutional predoctoral fellowship from the National Institutes of Health [grant number T32NS07433]. NDJ was supported by the Center for Neuroscience at the University of Pittsburgh Summer Undergraduate Research Program.

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Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Carly B. Fabian, Rebecca H. Cole, Lily G. Carley, Shannon M. Thompson, Marianne L. Seney & Max E. Joffe

  2. Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, PA, USA

    Carly B. Fabian, Rebecca H. Cole, Lily G. Carley, Shannon M. Thompson, Marianne L. Seney & Max E. Joffe

  3. Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

    Carly B. Fabian, Nilah D. Jordan, Rebecca H. Cole, Lily G. Carley, Shannon M. Thompson, Marianne L. Seney & Max E. Joffe

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Contributions

CBF: conceptualization, investigation, writing original draft, and visualization; NDJ: investigation; RHC: investigation; LGC: investigation; SMT: investigation and project administration; MLS: conceptualization and writing review and editing; and MEJ: conceptualization, investigation, writing-review and editing, supervision, and funding acquisition.

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Correspondence to Max E. Joffe.

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Fabian, C.B., Jordan, N.D., Cole, R.H. et al. Parvalbumin interneuron mGlu5 receptors govern sex differences in prefrontal cortex physiology and binge drinking. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01889-0

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