Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome

Lianne Robinson, Jacky Guy, Leanne McKay, Emma Brockett, Rosemary C. Spike, Jim Selfridge, Dina De Sousa, Cara Merusi, Gernot Riedel, Adrian Bird, Stuart R. Cobb*

*Corresponding author for this work

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Rett syndrome is a neurological disorder caused by mutation of the X-linked MECP2 gene. Mice lacking functional Mecp2 display a spectrum of Rett syndrome-like signs, including disturbances in motor function and abnormal patterns of breathing, accompanied by structural defects in central motor areas and the brainstem. Although routinely classified as a neurodevelop-mental disorder, many aspects of the mouse phenotype can be effectively reversed by activation of a quiescent Mecp2 gene in adults. This suggests that absence of Mecp2 during brain development does not irreversibly compromise brain function. It is conceivable, however, that deep-seated neurological defects persist in mice rescued by late activation of Mecp2. To test this possibility, we have quantitatively analysed structural and functional plasticity of the rescued adult male mouse brain. Activation of Mecp2 in similar to 70% of neurons reversed many morphological defects in the motor cortex, including neuronal size and dendritic complexity. Restoration of Mecp2 expression was also accompanied by a significant improvement in respiratory and sensory-motor functions, including breathing pattern, grip strength, balance beam and rotarod performance. Our findings sustain the view that MeCP2 does not play a pivotal role in brain development, but may instead be required to maintain full neurological function once development is complete.

Original languageEnglish
Pages (from-to)2699-2710
Number of pages12
JournalBrain
Volume135
Issue number9
Early online date23 Apr 2012
DOIs
Publication statusPublished - Sep 2012

Keywords

  • respiratory network
  • Rett syndrome
  • MECP2
  • breathing
  • motor function
  • synaptic plasticity
  • morphology
  • MECP2 mutant mice
  • brain
  • motor
  • CPG-binding protein-2
  • expression
  • dysfunction
  • disorders
  • neurons

Cite this

Robinson, L., Guy, J., McKay, L., Brockett, E., Spike, R. C., Selfridge, J., ... Cobb, S. R. (2012). Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome. Brain, 135(9), 2699-2710. https://doi.org/10.1093/brain/aws096