Thanks to the Simons Simplex Collection and other genetic cohorts of individuals with autism spectrum disorder (ASD), over 100 high-confidence risk genes have now been identified1. What is currently missing are mechanisms linking these genes into convergent pathways that give insight into disease etiology.
In the current proposal, Paul Jenkins and colleagues plan to test the hypothesis that proteins encoded by SCN2A and ANK2, two of the top ASD risk genes, are linked at the molecular level to control dendritic excitability. SCN2A encodes the alpha subunit of the neuronal voltage-gated sodium channel 1.2 (Nav1.2). It is 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 stability2. The timing of the subcellular relocalization of NaV1.2 away from the AIS (approximately one year in humans) also correlates with the onset of symptoms in individuals with ASD, suggesting that understanding the new role for Nav1.2 in dendrites may be critical for determining the etiology of SCN2A-associated ASD.
Jenkins’ group and others have shown that the intracellular scaffolding protein, ankyrin-G (encoded by the ANK3 gene), is necessary for NaV1.2 localization to the AIS3; however, very little is known about the mechanisms underlying the dendritic localization of NaV1.2. Ankyrin-B (the protein product of ANK2) is a member of the ankyrin gene family that shares significant homology with ankyrin-G, yet it is highly localized to dendrites, where it may play a key role in NaV1.2 dendritic localization.
Jenkins’s team aims to determine if ankyrin-B is the main scaffolding protein for dendritic Nav1.2 using mouse loss-of-function models and cultured mouse neurons. In addition, their group will explore the effects of disease-associated variants on protein-protein interactions and channel localization. Findings from these studies will increase our understanding of the mechanisms underlying synaptic alterations in ASD, which may provide novel targets for therapeutic intervention.
- CRISPR activation-based approach to rescue cellular and behavioral deficits associated with Scn2a haploinsufficiency
- Cellular and circuit effects of SCN2A haploinsufficiency
- In vivo calcium dynamics in dendritic spines of Shank3 and Scn2a mutant mouse models of autism
- Role of the autism risk gene Scn2a in oligodendrocyte-mediated myelination and circuit development