Rescuing cognitive deficits in alcohol-dependent mice by targeting physiological adaptations in prefrontal cortex KV7 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 KV7 channel modulation reduces alcohol intake in high-drinking rodents, but the impact of alcohol dependence on cortical KV7 physiology and its role in cognitive impairments are understudied. Here, we demonstrate spatial working memory deficits and physiological adaptations in intrinsic excitability and KV7 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 KV7 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.