Topic: p.A263V

Altered neuronal excitability in neurodevelopmental disorders can have profound implications for adult brain function. Understanding the critical time windows determining the clinical outcomes and lasting changes induced during these periods is therefore crucial. In our mouse model of developmental and epileptic encephalopathy (DEE) harboring a patient-derived Scn2a (p.A263V) mutation that results in a gain-of-function of Nav1.2 channels, Scn2a mutants exhibit a transient increase in excitability of hippocampal pyramidal neurons in vitro during the neonatal period. In vivo, homozygous Scn2a mu

SCN2A encodes the Nav1.2 voltage-gated sodium channel subunit, which is crucial for the initiation, propagation, and backpropagation of action potentials. During human and mouse brain development, Nav1.2 is the dominant axonal Nav isoform. Genetic SCN2A variants are associated with neurodevelopmental disorders such as epilepsy, ASD, ID, and schizophrenia. Nav1.2 gain-of-function variants have been shown to cause epilepsy and SUDEP, but the network changes driving epileptogenesis during development are not known. Given the dominant role of Nav1.2 during hippocampal development we hypothesize th

Our study investigates mechanisms of epileptogenesis caused by the p.A263V mutation in the SCN2A gene using a Scn2a p.A263V mouse model. The SCN2A gene is known for its role in neurodevelopmental disorders with epileptic presentations. Our objective is to understand the molecular foundations of neonatal neuronal hyperexcitability and its evolution into adult network disruptions, employing scRNA-seq. Neonatal homozygous (hom) mice showed seizures starting around P3, with heterozygous (het) mice also exhibiting early seizures. Despite recovery in het mice, persistent network alterations were obs