Description:

Paul Jenkins, Ph.D.
Assistant Professor, Department of Pharmacology
Assistant Professor, Department of Psychiatry
University of Michigan Medical School

"Molecular convergence of two high-risk autism genes in the control of dendritic excitability"

De novo genetic variants contribute significant risk for the development of autism spectrum disorders (ASD). Recent studies indicated that haploinsufficiency in Nav1.2 (SCN2A), one of the strongest risk alleles for ASD development, impairs dendritic excitability and synaptic function in neocortical pyramidal cells. However, how Nav1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B, product of another high-confidence ASD risk gene (ANK2), is essential for scaffolding Nav1.2 to the dendritic membrane of mouse neocortical neurons, and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/- conditions. Thus, 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 be etiological to neurodevelopmental disorder pathophysiology.