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

eNeuro. 2021 Jul 6;8(4):ENEURO.0056-21.2021. doi: 10.1523/ENEURO.0056-21.2021. Print 2021 Jul-Aug.

Abstract

The inflexible repetitive behaviors and "insistence on sameness" 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.

Keywords: ERK; MAPK; MECP2; autism; dendritic spine; spine clustering.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder*
  • Dendritic Spines / metabolism
  • Disease Models, Animal
  • MAP Kinase Signaling System
  • Mental Retardation, X-Linked*
  • Methyl-CpG-Binding Protein 2 / metabolism
  • Mice
  • Signal Transduction*
  • ras Proteins

Substances

  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • ras Proteins