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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 is essential for the top-down regulation of motivated behaviors. The activity of the prefrontal cortex is tightly controlled by parvalbumin-expressing interneurons, a key subpopulation of fast-spiking GABAergic cells that regulate cortical excitability through direct innervations onto the perisomatic regions of nearby pyramidal cells. Changes in prefrontal cortex parvalbumin-expressing interneurons have been implicated in the etiology of schizophrenia and other psychiatric disorders, and emerging work from preclinical models suggests these cells undergo sex-dependent adaptations following stress or binge drinking.

To improve our understanding of molecular mechanisms mediating such sex differences in parvalbumin-expressing interneuron function, University of Pittsburgh investigators including Carly Fabian, BS (neuroscience PhD student);  Marianne Seney, PhD (Associate Professor of Psychiatry); and Max Joffe, PhD (Assistant Professor of Psychiatry), focused on group 1 metabotropic glutamate (mGlu) receptors, mGlu1 and mGlu5, which are expressed on prefrontal cortex parvalbumin-expressing interneurons and regulate a variety of cellular processes related to membrane physiology, synaptic strength, and endocannabinoid plasticity. Combining whole-cell patch-clamp electrophysiology and selective pharmacology, they tested the hypothesis that mGlu1 and mGlu5 receptors mediate sex differences in prefrontal cortex parvalbumin-expressing interneurons function. 

“Our work was motivated by two key findings,” explained Ms. Fabian, first author of the study, which was published in Neuropsychopharmacology. “First, multiple studies, including ours, have shown that female mice drink more alcohol than males. Second, we previously identified sex-dependent changes in synaptic strength in parvalbumin interneurons following binge drinking. However, the molecular mechanisms driving these changes, and whether there are baseline sex differences, remain unexplored."

She added, "Group 1 mGlu receptors are ideally positioned to regulate synaptic strength in parvalbumin cells. Given the substantial literature linking these receptors to alcohol use disorder, we suspected they might play a role in the alterations observed after binge drinking."

The team found that parvalbumin-expressing interneurons from females exhibited lower rheobase and greater current-evoked spike-firing, while passive membrane properties, such as resting membrane potential and membrane resistance, did not differ between sexes. Although mGlu5 receptors mediate cell depolarization in parvalbumin-expressing cells from both sexes, only mGlu1 contributed to this effect in males. Additionally, synaptic strength onto parvalbumin cells were differentially regulated by mGlu1 and mGlu5.  Consistent with prior findings, female mice drank more than males. However, loss of mGlu5 receptor function on parvalbumin-expressing interneurons abrogated all sex differences in synaptic physiology and reduced binge-drinking in female, but not male mice. 

“These findings help describe sex differences in the mechanisms that regulate top-down control over drinking and other motivated behaviors. Furthermore, as compounds that modulate mGlu5 receptors are being investigated as novel antidepressants, antipsychotics, and analgesics, these findings suggest careful consideration of sex as a biological variable for these potential indications,” said Dr. Joffe, senior and corresponding author of the study.

Parvalbumin interneuron mGlu5 receptors govern sex differences in prefrontal cortex physiology and binge drinking
Fabian CB, Jordan ND, Cole RH, Carley LG, Thompson SM, Seney ML, Joffe ME.
Neuropsychopharmacology. (2024). https://doi.org/10.1038/s41386-024-01889-0