Delayed excitability recovery and downregulation of neurodevelopmental pathways contribute to phenotypic differences in KCNQ2‐related disorders

Abstract Objective Pathogenic variants in the KCNQ2 gene cause a spectrum of neonatal onset epilepsy, from self‐limited familial neonatal epilepsy (SeLNE; mild end) to developmental and epileptic encephalopathy (DEE; severe end). The associations and differences in the molecular mechanisms between the developmental outcomes of different KCNQ2 variants (SeLNE vs. DEE) remain unclear. Methods Using brain slice patch‐clamp and single‐nucleus RNA sequencing, we revealed developmental dysregulation in two different phenotypic Kcnq2 mice (DEE vs. SeLNE) during postnatal days 14–28 (P14–P28). Results Compared to wild‐type mice, both Kcnq2 ‐SeLNE and Kcnq2 ‐DEE mice exhibited neuronal hyperexcitability characterized by high‐frequency firing of action potentials. Notably, whereas SeLNE mice showed timely recovery of excitability, DEE mice displayed delayed restoration of abnormal excitability in CA1 excitatory neurons. During P14–P28, particularly at P21, DEE mice demonstrated significant downregulation of synaptic plasticity‐ and cognitive development‐related pathways in CA1 excitatory neuron subclusters (CA1.2/CA1.4 neurons). Conversely, SeLNE mice exhibited pronounced activation of neurodevelopmental signaling pathways. Transcriptomic analysis of differentially expressed genes between SeLNE and DEE mouse models revealed recurrent gene signatures, with persistent neuronal upregulation of Apoe in Kcnq2 ‐DEE mice. Significance This study identifies that the age‐related spontaneous remission of seizures is due to time‐limited changes in neuronal excitability, and treatment interventions for KCNQ2 ‐DEE patients need to consider critical developmental time windows. In the future, better therapeutic outcomes may be achieved through spatiotemporal transcriptional coordination with neurodevelopmental gene networks.