Rescuing cognitive deficits in alcohol-dependent mice by targeting physiological adaptations in prefrontal cortex K V 7 channels.

Chronic alcohol misuse causes cognitive deficits and functional adaptations in the prefrontal cortex (PFC) that facilitate excessive drinking and increase relapse probability during prolonged withdrawal. Positive K V 7 channel modulation reduces alcohol intake in high-drinking rodents, but the impact of alcohol dependence on cortical K V 7 physiology and its role in cognitive impairments are understudied. Here, we demonstrate spatial working memory deficits and physiological adaptations in intrinsic excitability and K V 7 channel function in intratelencephalic PFC projection neurons in alcohol-dependent mice. CRISPR-SaCas9 deletion of Kcnq3 in PFC neurons that project to the dorsomedial striatum mimicked physiological adaptations and working memory deficits produced by alcohol dependence. Furthermore, PFC microinfusion of the K V 7 positive modulator retigabine rescued alcohol-induced working memory dysfunction. These findings identify an aberrant cortical mechanism responsible for alcohol-associated cognitive dysfunction, providing insights into a pharmacological treatment approach that can target both high drinking and cognitive impairments associated with alcohol use disorder.