Thanks to the Simons Simplex Collection, the scientific community possesses dozens of highly reliable risk genes through the identification of rare de novo variants in patients with autism spectrum disorder (ASD). What is currently missing is a mechanism linking these genes into a convergent pathway that gives insight into disease etiology. In this proposal, we will test the hypothesis that ANK2 and SCN2A, two of the top genes implicated in ASD, are linked at the molecular level to control dendritic excitability. NaV1.2, product of the SCN2A gene, is a voltage-gated sodium channel found primarily in pyramidal neurons where it localizes to the axon initial segment (AIS) early in development. Later in development, NaV1.2 relocalizes to dendrites where it plays critical roles in synaptic plasticity and stability. The timing of the subcellular relocalization of NaV1.2 away from the AIS (~ 1 year in humans) also correlates with the onset of symptoms in ASD patients, suggesting that understanding the new role for NaV1.2 in dendrites may be critical for determining the etiology of SCN2A-associated ASD. While our group and others have shown that the intracellular scaffolding protein, ankyrin-G (ANK3), is necessary for NaV1.2 localization to the AIS, very little is known about the mechanisms underlying the dendritic localization of NaV1.2. Ankyrin-B, product of the ANK2 gene, is a member of the ankyrin gene family that shares significant homology with ankyrin-G, yet it is localized at high levels to dendrites where it may play a key role in NaV1.2 dendritic localization. Testing the hypothesis that ANK2 and SCN2A are linked at the molecular level to control dendritic excitability will have a positive impact by increasing our understanding of the mechanisms underlying synaptic alterations in ASD, which may provide novel targets for therapeutic intervention.

Narrative 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 two autism-linked genes ANK2 and SCN2A affect neuronal function. This project will shed light on the cellular and molecular mechanisms that contribute to the disorder, and potentially identify new avenues for therapeutic intervention.