Loss of KCNQ2 or KCNQ3 leads to multifocal time-varying activity in the neonatal forebrain ex vivo

Abstract

Early neonatal epileptic encephalopathy represents a group of epilepsies 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 Kcnq2 from forebrain excitatory neurons (Pyr:Kcnq2 mice) or constitutive deletion of Kcnq3 leads to sprawling hyperactivity across the neocortex. Surprisingly, the generation of time-varying hypersynchrony in slices from Pyr:Kcnq2 mice does not require fast synaptic transmission. This is in contrast to control littermates and constitutive Kcnq3 knockout mice where activity is primarily driven by fast synaptic transmission in the neocortex. Unlike in the neocortex, hypersynchronous activity in the hippocampal formation from Kcnq2 conditional and Kcnq3 constitutive knockout 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- and macro-circuit-specific manner.

SIGNIFICANCE STATEMENT

Neocortical hypersynchrony is a hallmark of neonatal epilepsy but its cellular mechanisms are unclear. This study shows that hypersynchrony in the neocortex can stem from the loss of KCNQ2 function in excitatory neurons even in the absence of fast synaptic transmission, unlike the hypersynchrony in response to KCNQ3 loss in the neocortex. This points to unique network dysfunctions involving potassium KCNQ2 channels as a mechanism for neonatal epilepsy.