Motor cortex plasticity in MeCP2 duplication syndrome

  • Awarded: 2012
  • Award Type: Research
  • Award #: 240069

Stelios Smirnakis and his team at Baylor College of Medicine in Houston, Texas, worked to understand how genetic defects in autism lead to malfunction at the circuit level. Understanding the mechanism of circuit malfunction will help generate new hypotheses on how to intervene to promote recovery.

Smirnakis and his group focused on MeCP2 duplication syndrome. Duplication of the MeCP2 (methyl-CpG-binding protein 2) gene causes a neurodevelopmental disorder in which affected boys manifest autism, intellectual disability and epilepsy. It has been hypothesized that these symptoms are mediated through the MeCP2 protein’s role as a master regulator of experience-dependent neural plasticity.

The researchers studied mice engineered to express MeCP2 at twice the normal level via transgenic insertion of the human MeCP2 gene (Tg1)1. The Tg1 mouse model recapitulates many features of the human disorder.  Their studies revealed increased dendritic branching and spine turnover in Tg1 mice compared with controls, suggesting the persistence of a relatively immature structural plasticity state. P70S6K, the main effector of the mTORC1 complex, was hyperphosphorylated in MeCP2 duplication animals, implicating enhanced mTOR signaling as a probable underlying mechanism2.

An important question is how abnormal structural plasticity manifests during learning. Both prominent behavioral inflexibility and, occasionally, exceptional learning abilities (‘savant’ phenotype) are seen in individuals with autism, but their substrate remains unexplained to date. Young adult MeCP2 duplication mice have an enhanced motor learning phenotype, giving researchers the opportunity to study this question.

Smirnakis and his team found that MeCP2 duplication animals show increased dendritic spine consolidation in clusters during motor learning. This was correlated with hyperactive Ras-MAPK and mTOR signaling. Remarkably, Ras-MAPK (ERK) phosphorylation inhibitors were able to reverse this phenotype at a dose that had no effect on the procedural learning of control animals. This work demonstrates how studying cortical circuit pathology can yield useful information about underlying molecular mechanisms, helping to improve specific behaviors.



1.Collins A.L. et al. Hum. Mol. Genet. 13, 2679-2689 (2004) PubMed
2.Jiang M. et al. J. Neurosci. 33, 19518-19533 (2013) PubMed
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