Kv7.2 Loss-of-Function Causes Early Hyperexcitability and Network Remodeling

Abstract

Loss-of-function (LOF) variants in the potassium channel subunit KCNQ2 cause a spectrum of neonatal epilepsies from self-limiting familial neonatal epilepsy (SeLFNE) to severe developmental and epileptic encephalopathy (DEE). To dissect the developmental consequences of KCNQ2 LOF, we conducted a longitudinal and multimodal comparative analysis in a human neuronal model generated from patients with KCNQ2-DEE and KCNQ2-SeLFNE. KCNQ2-LOF induced a biphasic network dysfunction, with early Kv7-driven hyperexcitability rescued by acute Retigabine (RTG) treatment, followed by maladaptive remodeling in the opposite direction. Transcriptomic analysis mirrored this biphasic dynamic trajectory, revealing an initial upregulation followed by a subsequent downregulation of synaptic genes. Structural analysis showed a steeper decline in presynaptic density alongside a distal shift in the axon initial segment (AIS) throughout maturation, and impaired AIS plasticity at later stages. Overall, KCNQ2-LOF disrupts human neuronal maturation through dynamic, biphasic changes in function, gene expression and structure, offering insights into disease mechanisms and therapeutic options.