Transient Neonatal Hyperexcitability Drives Persistent Network Alterations in Scn2a Mouse Model of Epilepsy
1 University of Cologne, Institute for Molecular & Behavioral Neuroscience, Cologne, Germany
2 University of Cologne, Institute for Molecular & Behavioral Neuroscience, Cologne, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Rapid changes in the nervous system during development render it more susceptible to any variations in neuronal excitability, which could lead to life-long consequences. Developmental and epileptic encephalopathies (DEEs) are characterized by early-onset seizures that frequently continue into adulthood, co-morbid with intellectual disability, autism, and developmental delay. Mutations in ion channels are one of the common epileptic etiologies. In this study, we focus on a p.A263V pathogenic variant of Nav1.2 sodium channel encoded by SCN2A. It is found de novo in patients with a range of conditions from benign self-limiting epilepsies to severe DEEs. Using Scn2a p.A263V mouse model and a variety of electrophysiological methods, including in vivo local field potential (LFP) neonatal and adult recordings, and electrocorticogram (ECoG) video telemetry, we investigated the impact of this mutation on cellular and network levels across developmental stages. Previously, in vitro recordings revealed a gene-dose dependent increase in excitability of hippocampal CA1 and CA3 pyramidal neurons in heterozygous and homozygous mutants aged from postnatal day 10 to 14 (P10-P14), normalized later in development (P24-P26). Consistent with this, in vivo we observed spontaneous electrographic seizures as early as P3. By P7 70% of heterozygous and 100% of homozygous mutants had seizures. After normalization of somatic excitability, only homozygous adult Scn2a mutants exhibited seizures, with 20% mortality during the 7 days of recording. Homozygous mutants also displayed more substantial changes in interictal activity. This included reduced mid-gamma oscillation frequency and increased theta phase shift across all hippocampal layers, as well as altered theta-gamma modulation in the middle molecular layer of the dentate gyrus, suggesting altered middle entorhinal cortical input. Altogether, this data indicates that transient neonatal hyperexcitability driven by the Scn2a p.A263V mutation induces lasting, gene dose-dependent network dysfunction. Informed by these results, we aim to reduce Scn2a level during early hyperexcitability via genetic approaches like CRISPRi and antisense oligonucleotides (ASOs) and use seizure activity and network oscillation alterations as outcome measures.