Convergent Inhibitory Cortical Circuit Disruption Drives Genetically Distinct Absence Seizures

Abstract

Childhood absence epilepsy is one of the most common pediatric epilepsies, characterized by brief involuntary lapse in consciousness and generalized spike-wave discharges (SWDs) on EEG. Despite a growing list of causative genes, the core cortical circuit abnormalities driving this highly stereotyped SWD phenotype remain elusive. Using two well-established absence epilepsy mouse models carrying point mutations in distinct genes altering pre and postsynaptic transmission, stargazer (Cacng2) and tottering (Cacna1a), we show that a specific translaminar inhibitory microcircuit defined by layer 6 corticothalamic neurons (L6 CT) and a novel Tac1+ Pvalb interneuron subtype is disrupted in both models. This early functional defect was followed by a secondary, marked dysfunction of deep-layer somatostatin-expressing (Sst) interneurons that coincides with the postnatal developmental onset of seizures. Crucially, we established the serial causality of these cascading defects by demonstrating that chemogenetic disruption of the L6 CT-Tac1+ Pvalb microcircuit alone in wild-type mice is sufficient to induce both the secondary Sst interneuron dysfunction and contemporaneous emergence of SWDs. Together, these findings reveal a sequential translaminar synaptic dysfunction or domino effect wherein a primary cell-autonomous defect triggers broader circuit adaptations permitting spike-wave hypersynchrony. Our results thus identify a convergent, causative cortical circuit pathology across two genetically heterogeneous absence epilepsy models, highlighting a common functional target for intervention