Parvalbumin interneurons mediate sex differences in prefrontal cortex function

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.

We recently set out to better characterize the molecular mechanisms that generate sex differences in PV-IN function by examining the function of metabotropic glutamate (mGlu) receptors in regulating PV-IN physiology [5]. In both female and male mice, the dual mGlu₁ and mGlu₅ agonist DHPG induced a slow, depolarizing current. Follow-up studies using selective antagonists revealed that mGlu₅ receptors preferentially depolarize PV-INs in female mice but that both mGlu₅ and mGlu₁ receptors can depolarize PV-INs in males (Figure 1). When examining synaptic transmission, we determined contrasting effects of mGlu₅ and mGlu₁ receptors in enhancing excitatory drive onto PV-INs in female and male mice, respectively. Finally, genetic deletion of mGlu₅ receptors from PV cells abrogated all sex differences in PV-IN physiology and signaling. Together, these findings indicate that mGlu₅ receptors are a key element dictating sex differences in PV-IN function.

Figure.

Left, In PFC PV-INs from male mice, mGlu₁ receptors depolarize cells enhance excitatory transmission. mGlu₅ receptors also depolarize cells and facilitate phasic endocannabinoid signaling via (2-AG). Right, In PV-INs from female mice, mGlu₁ does not affect membrane or synaptic properties. In addition, mGlu receptors do not facilitate phasic endocannabinoid signaling. Genetic deletion of mGlu₅ receptors from PV-INs eliminated all sex differences in PV-IN function. Abbreviations: 2-AG, 2-arachydonyl glycerol; DAGLa, diacylglycerol lipase alpha; mGlu, metabotropic glutamate; PFC, prefrontal cortex; PV-INs, parvalbumin-expressing interneurons.

Sex differences in mGlu receptor signaling are not observed in somatostatin interneurons or pyramidal cells, begging the question: which factors confer PV cells with pronounced sex differences? Several lines of evidence suggest that gonadal hormones are the most likely candidates. One of the sex hormone receptors, estrogen receptor β (ERβ), is expressed almost exclusively by PV-INs in the neocortex [2]. Furthermore, membrane-localized ERα/β are physically associated with mGlu_1/5 receptors, and these complexes regulate sex-specific signaling pathways [6]. Preclinical studies have linked the function of cortical PV-INs with several behavioral domains involved in psychiatric diseases, including working memory, social approach, and cognitive flexibility. Furthermore, post-mortem studies have identified changes in PV-INs in schizophrenia and autism spectrum disorders. Together, this evidence suggests that PV-INs may drive sex differences in psychiatric diseases. Understanding these relationships is essential for not only women’s health, as PV-INs convert testosterone to estradiol via aromatase. Continuing to identify the molecular mechanisms mediating sex differences in PV-IN function will improve our understanding of neuropsychiatric disease etiology and inform the development of new treatments.