Loss of KCNQ2 or KCNQ3 Leads to Multifocal Time-Varying Activity in the Neonatal Forebrain .

Epileptic encephalopathies represent a group of disorders often characterized by refractory seizures, regression in cognitive development, and typically poor prognosis. Dysfunction of KCNQ2 and KCNQ3 channels has emerged as a major cause of neonatal epilepsy. However, our understanding of the cellular mechanisms that may both explain the origins of epilepsy and inform treatment strategies for KCNQ2 and KCNQ3 dysfunction is still lacking. Here, using mesoscale calcium imaging and pharmacology, we demonstrate that in mouse neonatal brain slices, conditional loss of from forebrain excitatory neurons ( mice) or constitutive deletion of leads to sprawling hyperactivity across the neocortex. Surprisingly, the generation of time-varying hypersynchrony in slices from mice does not require fast synaptic transmission. This is in contrast to control littermates and constitutive knock-out mice where activity is primarily driven by fast synaptic transmission in the neocortex. Unlike in the neocortex, hypersynchronous activity in the hippocampal formation from conditional and constitutive knock-out mice persists in the presence of synaptic transmission blockers. Thus, we propose that loss of KCNQ2 or KCNQ3 function differentially leads to network hyperactivity across the forebrain in a region-specific and macro-circuit-specific manner.