The Effects of KV7 Channel Positive Modulation on Prefrontal Cortex Activity in Alcohol Dependent Mice

Alcohol use disorder (AUD) is a chronic relapsing brain disease characterized by compulsive alcohol use, withdrawal symptoms, and adaptations in the reward neurocircuitry. Evidence from previous studies have demonstrated that voltage-dependent KV7 potassium channels are a novel target for reducing alcohol seeking and behaviors commonly associated with AUD. However, the underlying changes in KV7 channel expression and function following chronic alcohol exposure are still largely unknown. We believe that cortical interneurons play a crucial role in these behavioral and neural adaptations. We utilized immunofluorescent staining procedures to quantify alterations in KV7 channel colocalization with one of the primary interneuron subtypes, parvalbumin, found in the prelimbic cortex (PL) following the induction of ethanol dependence. In addition, we used fiber photometry to record calcium transients in the PL of C57BL/6J mice that express the genetically encoded calcium indicator, GCaMP6. Calcium transients were recorded in freely moving mice in an open field apparatus that were treated with ML213, a selective KV7.2/7.4 channel positive modulator, prior to and following the induction of ethanol dependence. Consistent with our previous findings, ML213 altered PL activity in ethanol dependent but not in non-dependent animals. Analysis of the calcium transients of C57BL/6J mice expressing GCaMP6s under the control of a human synapsin (hSyn) promoter revealed very slow calcium transients at a frequency of 0.075 ± 0.01 events/second under basal conditions. However, the acute administration of ML213 following the induction of ethanol dependence increased the frequency and reduced amplitude of these calcium transients. These effects were not replicated in non-dependent nor in C57BL/6J mice expressing GCaMP6s selectively in glutamatergic neurons. These results provide evidence that the behavioral effects observed by KV7 channel positive modulation are influenced by possible adaptations on cortical interneurons. Our data suggest that KV7 channels are sensitized following ethanol dependence and allow for the coordination of interneuron activity in the PL