PT - JOURNAL ARTICLE AU - Ryan Thomas Ash AU - Shelly Alexandra Buffington AU - Jiyoung Park AU - Mauro Costa-Mattioli AU - Huda Yaya Zoghbi AU - Stelios Manolis Smirnakis TI - Excessive ERK-dependent synaptic clustering drives enhanced motor learning in the MECP2 duplication syndrome mouse model of autism AID - 10.1101/100875 DP - 2017 Jan 01 TA - bioRxiv PG - 100875 4099 - http://biorxiv.org/content/early/2017/01/16/100875.short 4100 - http://biorxiv.org/content/early/2017/01/16/100875.full AB - Autism-associated genetic mutations may produce altered learning abilities by perturbing the balance between stability and plasticity of synaptic connections in the brain. Here we report an increase in the stabilization of dendritic spines formed during repetitive motor learning in the mouse model of MECP2-duplication syndrome, a high-penetrance form of syndromic autism. This increased stabilization is mediated entirely by spines that form cooperatively in clusters. The number of clusters formed and stabilized predicts the mutant’s enhanced motor learning and memory phenotype, reminiscent of savant-like behaviors occasionally associated with autism.The ERK signaling pathway, which promotes cooperative plasticity between spines, was found to be hyperactive in MECP2-duplication motor cortex specifically after training. Inhibition of ERK signaling normalizes clustered spine stabilization and rescues motor learning behavior in mutants. We conclude that learning-associated dendritic spine clustering stabilized by hyperactive ERK signaling drives abnormal motor learning and memory consolidation in this model of syndromic autism.