Parvalbumin interneuron mGlu₅receptors govern sex differences in prefrontal cortex physiology and binge drinking

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. Proper function of the prefrontal cortex (PFC) is essential for the top-down regulation of motivated behaviors. 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 mGlu1and mGlu5metabotropic glutamate receptors regulate cell excitability, excitatory drive, and endocannabinoid signaling at PFC PV-INs in a sex-dependent manner. Genetic deletion of mGlu5receptors 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 mGlu1and mGlu5receptors as candidate signaling molecules involved in sex differences in PV-IN activity and behaviors relevant for alcohol use.

Metabotropic signaling within somatostatin interneurons controls transient thalamocortical inputs during development

“…3e). The high mGluR1 level expression at P30 suggests that mGluR1 specificity in SST cINs decreases over time through the acquisition of mGluR1 expression in other cell types, as recently described at adulthood 44,45 . These data nominate mGluR1 as a candidate for triggering metabotropic postsynaptic signaling in SST cINs to control transient TC inputs during early postnatal development.…”