PT  - JOURNAL ARTICLE
AU  - Perry WE Spratt
AU  - Roy Ben-Shalom
AU  - Caroline M Keeshen
AU  - Kenneth J Burke, Jr.
AU  - Rebecca L Clarkson
AU  - Stephan J Sanders
AU  - Kevin J Bender
TI  - The autism-associated gene <em>Scn2a</em> plays an essential role in synaptic stability and learning
AID  - 10.1101/366781
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 366781
4099  - http://biorxiv.org/content/early/2018/07/10/366781.short
4100  - http://biorxiv.org/content/early/2018/07/10/366781.full
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.