Sodium Channel Dysfunction in Altered Brain Development - Project Summary Ion channel dysfunction is a leading cause of malformations in cortical development (MCDs), resulting in severe neurological disorders and disability. In particular, findings from our group and others have indicated a crucial role for sodium channel subtypes and ion transporters in early human brain development, suggesting that ion channel diseases affecting children likely have prenatal pathology prior to diagnosis after birth. Importantly, several pathogenic variants of the voltage-gated sodium channel subtypes SCN2A and SCN3A produce complex, non-overlapping phenotypes of abnormal brain development. For example, we found severe gain-of- function (GoF) SCN2A variants associated with MCDs and seizures, in contrast to other GoF SCN2A variants associated with developmental and epileptic encephalopathy. These distinct SCN2A variant phenotypes lead us to hypothesize that the level of GoF sodium influx could result in dose dependent effects at different stage of perinatal development. To investigate cellular and biophysical SCN2A pathologies during prenatal development, we established transient transgenic ferrets as a validated system to phenocopy human MCDs. Unlike mice, ferrets possess a human-like neocortex with developmental cell types and brain folds (gyri and sulci) critical for cognitive function. Utilizing transient transgenic ferrets, we propose to examine novel SCN2A variants associated with severe neurodevelopmental disease to define the prenatal (Aim 1) and postnatal (Aim 2) onset and biological basis for SCN2A-associated disorders. Establishing the early pathological origins of SCN2A-associated diseases (e.g. effects on proliferation, cell fate, migration, and action potential kinetics) is necessary for developing treatments that intervene prior to irreversible brain changes. In addition, this work will provide a critical window to examine fundamental processes of cortex development regulated in utero by sodium channel activity.
