Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites

Abstract

Dysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes SCN2A, which encodes the sodium channel Na_V1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how Na_V1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding Na_V1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a^+/- conditions. These results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can contribute to neurodevelopmental disorder pathophysiology.

Keywords: ankyrin; autism spectrum disorder; axon initial segment; convergence; dendrite; excitability; localization; medial prefrontal cortex; sodium channel; synapse.