Parvalbumin interneuron activation rescues both seizures and impaired social novelty in digenic absence epilepsy mice.

Abstract

Childhood absence epilepsy (CAE) is a common genetic epilepsy with a frequently complex polygenic etiology, for which a genetically tractable animal model is lacking. Current anti-seizure medications fail to address the significant neurocognitive and social comorbidities of CAE, highlighting a critical unmet need for comprehensive therapies and a better understanding of the underlying mechanisms. To address this, we developed a digenic mouse model (<i>Cacng2</i>^stargazer/+;<i>Cacna1a</i>^+/-, hereafter DiG^stg+Ca1A) that mimics human polygenicity. The double mutant mice exhibit both absence seizures and altered social novelty preference. We found that ethosuximide, a first-line anti-CAE medication targeting thalamic low-threshold T-type calcium currents, suppressed seizures in DiG^stg+Ca1A mice but failed to rescue their social deficit. Similarly, deletion of <i>Cacna1g</i>, which encodes the T-type Ca²⁺ channel Ca_V3.1, prevented seizure generation but did not ameliorate the social deficit. These findings reveal a dissociation between the T-type current that mediates seizures and the mechanism underlying the social deficits. We further demonstrate that in <i>Cacng2</i>^stargazer/+ mice, selective deletion of one copy of <i>Cacna1a</i> in stargazin-enriched parvalbumin (PV) interneurons induced absence seizures and impaired social behavior. Remarkably, chemogenetic activation of cortical and thalamic PV interneurons using DREADDs not only suppressed seizures but also rescued the impaired social behavior. Together, our results suggest that selective modulation of PV interneuron activity in polygenic absence epilepsy could serve as a promising therapeutic strategy to address both absence seizures, and the often treatment-resistant neurocognitive comorbidities observed in CAE.