Alcohol dependence-induced neuroadaptations in prelimbic K _V 7 channels contribute to working memory deficits in mice

Chronic alcohol use can cause executive function deficits, such as diminished working memory, which can facilitate excessive alcohol intake and elevate relapse probability even in prolonged withdrawal. Unfortunately, current FDA-approved medications for alcohol use disorder (AUD) are not designed to also treat alcohol-induced cognitive dysfunction. K _V 7 channels are a class of voltage-gated potassium channels that regulate neuronal excitability and are implicated in cognitive function. K _V 7 channels are sensitive to acute and chronic alcohol exposure, and positive K _V 7 channel modulation reduces alcohol intake in high-drinking rodents. The impact of chronic alcohol exposure on K _V 7 physiology in the prelimbic cortex (PL), a region essential for cognitive function, remains unexplored. To address this, cognitive deficits were measured in male and female mice following the chronic intermittent ethanol (CIE) model of alcohol dependence using a delayed alternation working memory task. After establishing that CIE elicits cognitive deficits regardless of sex, whole-cell patch clamp electrophysiology recordings were performed on distinct PL pyramidal neurons; intratelencephalic (IT neurons) and extratelencephalic (ET neurons) projection neurons to measure K _V 7 channel mediated M-currents, along with evoked action potential firing following chronic intermittent ethanol (CIE) exposure in male and female mice. CIE exposure led to an increase in intrinsic excitability and a decrease in M-current regardless of sex, which was largely driven by CIE-induced adaptations in IT neurons. These neural adaptations in dependent mice coincided with the emergence of working memory deficits. Microinjections of the K _V 7 positive modulator retigabine restored working memory function in male and female CIE-exposed mice. Together, these results indicate that chronic alcohol downregulates K _V 7 function within distinct cortical cell types, and that K _V 7 modulation may be a promising pharmacological treatment for alcohol induced cognitive impairment.