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Parvalbumin interneurons mediate sex differences in prefrontal cortex function

Neuropsychopharmacology (2025)Cite this article

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Psychiatric diseases involving prefrontal cortex (PFC) function exhibit sex differences in incidence and severity. For instance, women are more likely to develop major depressive disorder, while schizophrenia and autism spectrum disorder are more common in men. Moreover, even when diagnosed with the same disease, men and women often experience different presentations and responses to treatments. These findings reaffirm clear and compelling rationale for thorough assessments of sex as a biological variable.

Parvalbumin-expressing interneurons (PV-INs) regulate PFC functions and are implicated in the etiology of many psychiatric disorders. Notably, an increasing body of literature indicates that sex-specific molecular mechanisms guide how PV-INs function in neural circuits and regulate behavior. Indeed, prior evidence from our lab [1] and others [2] indicates that neocortical PV-INs from female mice are more excitable than PV-INs from males. Further, manipulations that affect GABA transmission or G protein-coupled receptor signaling in PV-INs can drive sex-specific behavioral effects. In addition, PV-INs display sex differences in circadian rhythms [3], as well as susceptibility to early life adversity and other disease-relevant experiences [4]. Together, these findings suggest that PV-INs are a key cell type mediating sex differences in PFC function.

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Acknowledgements

We thank members of the Seney and Joffe labs for helpful and stimulating discussions. Support was provided by the National Institutes of Health [grant numbers R00AA027806 and MH120066] and the Brain and Behavior Research Foundation.

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Authors and Affiliations

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

    Marianne L. Seney & Max E. Joffe

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

    Marianne L. Seney & Max E. Joffe

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

    Marianne L. Seney & Max E. Joffe

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  1. Marianne L. Seney
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  2. Max E. Joffe
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MLS—Conceptualization, Writing—Review & Editing; MEJ—Conceptualization, Writing—Review & Editing.

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Correspondence to Marianne L. Seney or Max E. Joffe.

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Seney, M.L., Joffe, M.E. Parvalbumin interneurons mediate sex differences in prefrontal cortex function. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02186-0

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  • DOI: https://doi.org/10.1038/s41386-025-02186-0

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