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

01/08/2026

AI Summary

Digenic DiGstg+Ca1A mice exhibit absence seizures and impaired social novelty, modelling polygenic childhood absence epilepsy.
Ethosuximide and Cacna1g deletion suppress seizures but fail to rescue social deficits, revealing dissociation between seizure T-type currents and social pathology.
Chemogenetic activation of cortical and thalamic parvalbumin interneurons suppresses seizures and rescues impaired social behaviour, indicating PV modulation as therapeutic strategy.

TL;DR (AI Generated)

We found that ethosuximide, a first-line anti-CAE medication targeting thalamic low-threshold T-type calcium currents, suppressed seizures in DiGstg+Ca1A mice but failed to rescue their social deficit.

We further demonstrate that in Cacng2stargazer/+ mice, selective deletion of one copy of Cacna1a in stargazin-enriched parvalbumin (PV) interneurons induced absence seizures and 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.

Basic summary

Sci Adv. 2026 Jul 31;12(31):eaec6065. doi: 10.1126/sciadv.aec6065. Epub 2026 Jul 31.

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 (Cacng2^stargazer/+;Cacna1a^+/-, 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 Cacna1g, 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 Cacng2^stargazer/+ mice, selective deletion of one copy of Cacna1a 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.