Abstract

Absence seizures, the most common childhood epilepsy, are characterized by brief involuntary lapses in consciousness and 3-Hz spike-wave EEG discharges (SWD). Despite extensive documentation of pathogenic thalamic remodeling, the cortical circuit abnormalities driving this highly stereotyped SWD remain elusive. Using two of the best characterized mouse models of absence epilepsy carrying point mutations in distinct genes altering pre and postsynaptic transmission, stargazer (Cacng2) and tottering (Cacna1a), we show that a specific translaminar inhibitory circuit motif defined by layer 6 corticothalamic neurons (L6 CT) and a novel Tac1+ Pvalb interneuron subtype is selectively disrupted in both models. This early functional defect was accompanied by a secondary synaptic collapse of deep-layer somatostatin-expressing (Sst) interneurons that precisely coincides with the developmental onset of seizures. Crucially, we established the serial causality of these cascading defects by demonstrating that chemogenetic disruption of L6 CT-Tac1+ Pvalb circuit motif alone in wild-type mice is sufficient to induce both the secondary Sst interneuron collapse and contemporaneous emergence of SWDs. Together, these findings reveal a sequential translaminar synaptic failure, or domino effect, wherein a primary defect triggers broader circuit adaptations permitting spike-wave hypersynchrony. Our results thus identify a convergent, causative cortical circuit pathology that is shared by genetically heterogeneous absence epilepsy models, highlighting a common functional target for therapeutic intervention.