Reversibility and Mapping of Rett Syndrome-like Phenotypes in the Mouse Brain

Lead Research Organisation: University of Edinburgh
Department Name: Unknown

Abstract

Autism includes a family of brain conditions that affect about 1% of all children. While there is strong evidence that these disorders are genetic in origin, the genes responsible are in almost all cases unknown. Rett Syndrome belongs to the autism family because affected individuals show late onset symptoms including repetitive hand movements, lack of speech and mental retardation. Rett is exceptional, however, because we know that the root cause is virtually always due to mutation of a known gene: MECP2. Mice that have the same mutation show symptoms very similar to Rett Syndrome, permitting us to study the disease in depth. We made the surprising finding last year that mice with advanced Rett-like symptoms could be rescued by switching on the MECP2 gene. In other words Rett Syndrome, in mice at least, is highly reversible. Here we wish to build on that study by applying sensitive tests for many aspects of brain function. Using these tests will be able to see how reversible each Rett-like symptom is and to find out which region of the brain is responsible. By mapping symptoms onto the brain in this way, we hope to set the stage for targeted therapies that may treat specific defects in Rett and perhaps related autistic conditions.

Technical Summary

Rett Syndrome is a monogenic autism spectrum disorder caused by mutations in the X-linked MECP2 gene. A mouse model created by disruption of the Mecp2 gene recapitulates many features of Rett and offers a potential route to understanding this disorder. In 2007, our laboratory made the unexpected discovery that activation of a previously silent Mecp2 gene caused almost complete reversal of advanced neurological symptoms in mice. This demonstrated that absence of MeCP2 protein during development does not lead to irrevocable defects in the brain. The present proposal seeks to quantify phenotypic reversal more rigorously using a battery of behavioural, neuroanatomical and electrophysiological assays. Using this new information, we will go on to map aspects of the Rett-like phenotype onto the brain, by following the effects of inactivating or activating Mecp2 exclusively in specific brain regions. In these same neuronal subsets, we will then analyse the effects of MeCP2-deficiency on gene expression and will map MeCP2 binding sites. Furthermore, we will ask whether MeCP2-positive neurons, which are intermingled with MeCP2-negative neurons in the brains of Rett patients, are physiologically adversely affected by neurons expressing the mutant protein. In other words, are the deleterious effects of mutant MeCP2 cell autonomous? Together, these experiments are designed to advance our understanding of Rett Syndrome and to impact future approaches to therapy of Rett and related disorders.

Publications

10 25 50
 
Description School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact More than 50 students attended a scientific careers talk and were encouraged to participate in discussions afterwards.

None
Year(s) Of Engagement Activity 2009,2010,2011