@article {AshENEURO.0056-21.2021, author = {Ryan Thomas Ash and Shelly Alexandra Buffington and Jiyoung Park and Bernhard Suter and Mauro Costa-Mattioli and Huda Yaya Zoghbi and Stelios Manolis Smirnakis}, title = {Inhibition of Elevated Ras-MAPK Signaling Normalizes Enhanced Motor Learning and Excessive Clustered Dendritic Spine Stabilization in the MECP2-Duplication Syndrome Mouse Model of Autism}, elocation-id = {ENEURO.0056-21.2021}, year = {2021}, doi = {10.1523/ENEURO.0056-21.2021}, publisher = {Society for Neuroscience}, abstract = {The inflexible repetitive behaviors and {\textquotedblleft}insistence on sameness{\textquotedblright} seen in autism imply a defect in neural processes controlling the balance between stability and plasticity of synaptic connections in the brain. It has been proposed that abnormalities in the Ras-ERK/MAPK pathway, a key plasticity-related cell signaling pathway known to drive consolidation of clustered synaptic connections, underlie altered learning phenotypes in autism. However, a link between altered Ras-ERK signaling and clustered dendritic spine plasticity has yet to be explored in an autism animal model in vivo. The formation and stabilization of dendritic spine clusters is abnormally increased in the MECP2-duplication syndrome mouse model of syndromic autism, suggesting that ERK signaling may be increased. Here, we show that the Ras-ERK pathway is indeed hyperactive following motor training in MECP2-duplication mouse motor cortex. Pharmacological inhibition of ERK signaling normalizes the excessive clustered spine stabilization and enhanced motor learning behavior in MECP2-duplication mice. We conclude that hyperactive ERK signaling may contribute to abnormal clustered dendritic spine consolidation and motor learning in this model of syndromic autism.Significance StatementIt has been proposed that autism-associated genetic mutations lead to altered learning phenotypes by perturbing cell signaling pathways that regulate synaptic plasticity in the brain. The Ras-ERK/MAPK signaling pathway, which promotes stabilization of dendritic spine clusters, has been particularly implicated in autism spectrum disorder (ASD). Here, we show that Ras-ERK signaling is increased in motor cortex following rotarod training in the MECP2-duplication syndrome mouse model of autism, and that the abnormal motor learning and excessive stabilization of clustered dendritic spines previously observed in MECP2-duplication mice can be rescued by pharmacological inhibition of Ras-ERK signaling. This provides additional support to hypotheses that autistic phenotypes arise from disrupted Ras-ERK signaling and synaptic plasticity and suggest potential future paths for therapeutic intervention.}, URL = {https://www.eneuro.org/content/early/2021/05/19/ENEURO.0056-21.2021}, eprint = {https://www.eneuro.org/content/early/2021/05/19/ENEURO.0056-21.2021.full.pdf}, journal = {eNeuro} }