RT Journal Article SR Electronic T1 The autism-associated gene Scn2a plays an essential role in synaptic stability and learning JF bioRxiv FD Cold Spring Harbor Laboratory SP 366781 DO 10.1101/366781 A1 Perry WE Spratt A1 Roy Ben-Shalom A1 Caroline M Keeshen A1 Kenneth J Burke, Jr. A1 Rebecca L Clarkson A1 Stephan J Sanders A1 Kevin J Bender YR 2018 UL http://biorxiv.org/content/early/2018/07/10/366781.abstract AB 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 NaV1.2, 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 NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons, in addition to regulating early developmental axonal excitability. NaV1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic stability, even when NaV1.2 expression was disrupted late in development. Furthermore, we identified behavioral impairments in learning and sociability, paralleling observations in children with SCN2A loss. These results reveal a novel dendritic function for NaV1.2, providing insight into cellular mechanisms likely underlying circuit and behavioral dysfunction in ASD.