The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex

Autism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein Na(V)1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here we show that Na(V)1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons in addition to regulating early developmental axonal excitability. Na(V)1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic strength, even when Na(V)1.2 expression was disrupted in a cell-autonomous fashion late in development. These results reveal a novel dendritic function for Na(V)1.2, providing insight into cellular mechanisms probably underlying circuit and behavioral dysfunction in ASD.