Contrasting adaptations to synaptic physiology of prefrontal cortex interneuron subtypes in a mouse model of binge drinking

Abstract

Alcohol use disorder (AUD) affects all sexes, however women who develop AUD may be particularly susceptible to cravings and other components of the disease. While many brain regions are involved in AUD etiology, proper function of the prefrontal cortex (PFC) is particularly important for top-down craving management and the moderation of drinking behaviors. Essential regulation of PFC output is provided by local inhibitory interneurons, yet the effects of chronic drinking on interneuron physiology remain poorly understood, particularly in female individuals. To address this gap, we generated fluorescent reporter transgenic mice to label the two major classes of interneuron in deep layer prelimbic PFC, based on expression of parvalbumin (PV-IN) or somatostatin (SST-IN). We then interrogated PV-IN and SST-IN membrane and synaptic physiology in a rodent model of binge drinking. Beginning in late adolescence, mice received 3-4 weeks of intermittent access (IA) ethanol. One day after the last drinking session, adaptations to PV-IN and SST-IN intrinsic physiology were observed in male mice but not in female mice. Furthermore, IA ethanol precipitated diametrically opposing changes to PV-IN synaptic physiology based on sex. IA ethanol decreased excitatory synaptic strength onto PV-INs from female mice and potentiated excitatory transmission onto PV-INs male mice. In contrast, decreased synaptic strength onto SST-INs was observed following IA ethanol in all groups of mice. Together, these findings illustrate novel sex differences in drinking-related PFC pathophysiology. Discovering means to restore PV-IN and SST-IN dysfunction following extended drinking provides opportunities for developing new treatments for all AUD patients.