Title: The function of SCN2A in autism spectrum disorder Project Summary: Mutations identified by exome sequencing demonstrate that disruption of the sodium channel SCN2A is strongly associated with autism spectrum disorder. SCN2A encodes the neuronal sodium channel NaV1.2, which is expressed at the site of action potential initiation. More recently, we have discovered that these channels are likely expressed throughout neocortical excitatory neuron dendrites, and that their dendritic function may be consequential to synaptic maturation and plasticity. Here, we will use a complement of electrophysiology, 2-photon imaging, and compartmental modeling to determine how heterozygous and homozygous loss of function of Scn2a affects the integrative properties of neurons. Furthermore, we will use novel mouse models and genetic techniques to ask whether changes in Scn2a expression levels in particular cell classes and developmental stages alters neuronal function. Results of this study will provide critical insight into how mutations in SCN2A contributes to autism spectrum disorder and the activity dependent development of cortical circuits.

Relevance Autism spectrum disorder is an early onset, life-long disorder that affects approximately 1% of the population and is defined by fundamental impairments in social communication and restricted or repetitive behavior or interests. This work focuses on understanding how dysfunctions in the autism-linked gene SCN2A, which encodes a neuronal sodium channel, affects neuronal function. This project will shed light on the cellular and circuit mechanisms that contribute to the disorder, and potentially identify developmental timepoints for therapeutic intervention.