Prefrontal PV interneurons facilitate attention and are linked to attentional dysfunction in a mouse model of absence epilepsy

Absence seizures are characterized by brief periods of unconsciousness accompanied by a lapse in motor function that can occur hundreds of times throughout the day. Outside of these frequent moments of unconsciousness, approximately a third of patients experience treatment-resistant attention impairments. Convergent evidence suggests prefrontal cortex (PFC) dysfunction may underlie attention impairments in affected patients. To test this, we use a combination of slice physiology, fiber photometry, electrocorticography (ECoG), optogenetics, and behavior in the Scn8a+/- mouse model of absence epilepsy. In these mice, we find decreased parvalbumin interneuron (PVIN) recruitment in the medial PFC (mPFC) in vitro and hypoactivity during cue presentation in vivo that is linked to attention dysfunction. Further, we find that low levels of mPFC PVIN activity are predictive of poorer performance in WT littermates. This highlights cue-evoked PVIN activity as an important mechanism for attention and suggests PVINs may represent a therapeutic target for cognitive comorbidities in absence epilepsy.