Kv7.2 loss-of-function causes early hyperexcitability and network remodelling.

Abstract

Loss-of-function (LOF) variants in KCNQ2, encoding the potassium channel subunit Kv7.2, cause a spectrum of neonatal epilepsies ranging from self-limiting familial neonatal epilepsy (SeLFNE) to severe developmental and epileptic encephalopathy (DEE). To dissect the developmental consequences of Kv7.2 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 variants induced a biphasic dysfunction at both single-cell and network levels, characterized by early Kv7-driven hyperexcitability accompanied by a clear reduction M-current density, which was rescued by acute Retigabine treatment. At later stages, intrinsic excitability and M-current normalized, yet network activity diverged further from control trajectories, indicating compensatory and ultimately maladaptive network remodeling. 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 variants disrupt human neuronal maturation through dynamic, biphasic changes in function, gene expression and structure, offering insights into disease mechanisms and therapeutic options.