Mechanisms of SCN3A-neurodevelopmental disorder in a mouse model

PROJECT SUMMARY/ABSTRACT SCN3A-related neurodevelopmental disorder (SCN3A-NDD) is a newly identified syndrome characterized by a spectrum of clinical phenotypes including treatment resistant epilepsy, intellectual disability and developmental delay, and malformation of cortical development. SCN3A-NDD is caused by pathogenic variation in the gene SCN3A which encodes Nav1.3, the predominant voltage gated sodium (Na+) channel a subunit expressed in the embryonic brain. Yet, a role for Na+ channels in regulating brain development has yet to be established and the physiological function of Nav1.3 throughout development and in the early postnatal brain remains largely unknown. This proposal will employ a novel preclinical mouse model to gain deeper insight into the pathophysiology of SCN3A-NDD while advancing the development of effective therapeutic interventions for treatment of this devastating disorder. In this study I will use a novel mouse model of SCN3A-NDD to evaluate how pathogenic variation in Nav1.3 alters the excitability of neurons and leads to the clinical features observed in SCN3A-NDD. First, I will evaluate the manifestation of the core features of SCN3A-NDD in the mouse model by examining developmental milestones, seizure susceptibility/epilepsy, and neuroanatomy (Aim 1). I will then determine the effects of pathogenic variation of Nav1.3 on the electrophysiological properties of neurons and their underlying sodium currents and utilize pharmacology to attempt to ameliorate the cellular phenotype (Aim 2). Lastly, I will temporally manipulate pathogenic Nav1.3 expression to determine the critical window of Nav1.3 pathogenicity and employ pharmacology and antisense oligonucleotides (ASO) to assess the effects of reduced Scn3a levels on phenotypes of SCN3A-NDD in vivo (Aim 3). This proposed study will advance understanding of the mechanistic underpinnings of SCN3A-NDD while also offering insight to a potential novel role of sodium channels in normal brain development. This work will provide me with training in electrophysiological and pharmacological techniques in a mouse model of neurodevelopmental disease which will advance my training towards a career in translational neuroscience research.