Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):2029-34. doi: 10.1073/pnas.0812394106.

Abstract

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. Here we show that systemic treatment of MeCP2 mutant mice with an active peptide fragment of Insulin-like Growth Factor 1 (IGF-1) extends the life span of the mice, improves locomotor function, ameliorates breathing patterns, and reduces irregularity in heart rate. In addition, treatment with IGF-1 peptide increases brain weight of the mutant mice. Multiple measurements support the hypothesis that RTT results from a deficit in synaptic maturation in the brain: MeCP2 mutant mice have sparse dendritic spines and reduced PSD-95 in motor cortex pyramidal neurons, reduced synaptic amplitude in the same neurons, and protracted cortical plasticity in vivo. Treatment with IGF-1 peptide partially restores spine density and synaptic amplitude, increases PSD-95, and stabilizes cortical plasticity to wild-type levels. Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation.

Publication types

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

MeSH terms

  • Action Potentials
  • Animals
  • Brain
  • Disease Models, Animal
  • Heart Rate
  • Insulin-Like Growth Factor I / pharmacology*
  • Insulin-Like Growth Factor I / therapeutic use
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Mice
  • Mice, Mutant Strains
  • Motor Activity
  • Neurons
  • Organ Size
  • Rett Syndrome / drug therapy*
  • Survival Rate
  • Synaptic Transmission
  • Treatment Outcome

Substances

  • Methyl-CpG-Binding Protein 2
  • Insulin-Like Growth Factor I