Sex differences in the medial prefrontal cortical glutamate system

Abstract

Background Dysregulation in the prefrontal cortex underlies a variety of psychiatric illnesses, including substance use disorder, depression, and anxiety. Despite the established sex differences in prevalence and presentation of these illnesses, the neural mechanisms driving these differences are largely unexplored. Here, we investigate potential sex differences in glutamatergic transmission within the medial prefrontal cortex (mPFC). The goal of these experiments was to determine if there are baseline sex differences in transmission within this region that may underlie sex differences in diseases that involve dysregulation in the prefrontal cortex. Methods Adult male and female C57Bl/6J mice were used for all experiments. Mice were killed and bilateral tissue samples were taken from the medial prefrontal cortex for western blotting. Both synaptosomal and total GluA1 and GluA2 levels were measured. In a second set of experiments, mice were killed and ex vivo slice electrophysiology was performed on prepared tissue from the medial prefrontal cortex. Spontaneous excitatory postsynaptic currents and rectification indices were measured. Results Females exhibit higher levels of synaptosomal GluA1 and GluA2 in the mPFC compared to males. Despite similar trends, no statistically significant differences are seen in total levels of GluA1 and GluA2. Females also exhibit both a higher amplitude and higher frequency of spontaneous excitatory postsynaptic currents and greater inward rectification in the mPFC compared to males. Conclusions Overall, we conclude that there are sex differences in glutamatergic transmission in the mPFC. Our data suggest that females have higher levels of glutamatergic transmission in this region. This provides evidence that the development of sex-specific pharmacotherapies for various psychiatric diseases is important to create more effective treatments.

Maternal fluoxetine impairs synaptic transmission and plasticity in the medial prefrontal cortex and alters the structure and function of dorsal raphe nucleus neurons in offspring mice

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Harnessing axonal transport to map reward circuitry: Differing brain-wide projections from medial forebrain domains

“…Some limitations of this study include differences between the two cohorts that may influence their forebrain projections, including gender mix and pre-injection history. Some evidence suggests that female gender affects mPFC (Knouse et al, 2022), although we have not found differences in previous work comparing MEMRI data between genders (Uselman et al, 2020). This result could have been due to a lower sensitivity to such gender-dependent effects in our methodology.…”

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

“…The prefrontal cortex (PFC) provides top-down regulation of motivated behaviors and displays sex differences in form and function [10][11][12][13][14]. Most PFC neurons are glutamatergic pyramidal cells that send, receive, and integrate information to and from various subcortical and cortical structures [15,16].…”