Rett Syndrome is a devastating developmental disorder due in most cases to mutation of the gene Mecp2. Affected individuals lose or fail to develop many normal language, motor and cognitive abilities. Mutant mice lacking part or all of the gene recapitulate many features of the human disease. However, the precise molecular and cellular interactions by which Mecp2 causes disease remain largely unknown. We found recently that mice lacking normal Mecp2 have reduced cortical activity due to a shift in the balance between excitation and inhibition. We also found that gene expression is altered in cortical neurons, but that different sets of genes are affected in different neuronal cell types. We will determine if this effect of loss of Mecp2 is more general by examining gene expression in several other cell types and will identify which changes occur earliest in development. Rett patients have severe learning disabilities and Mecp2 mutant mice show altered synaptic plasticity. The defects in synaptic plasticity could be primary effects of loss of Mecp2 function, or could be secondary to changes in brain circuitry. In order to decide between these possibilities we will examine long- term potentiation and depression at individual synaptic connections under conditions that minimize the potential impact of other changes in the circuit. We will also examine a homeostatic form of plasticity called synaptic scaling. This is a plasticity mechanism that normally keeps cortical networks stable in the face of changing activity levels. Disruption of scaling could contribute to altered activity levels following loss of Mecp2 function. Finally, we will determine whether or not the changes in gene expression and physiology observed in mice that lack Mecp2 altogether, also occur in heterozygous mice that lack only one copy of Mecp2.
| Rutlin, Michael; Nelson, Sacha B (2011) MeCP2: phosphorylated locally, acting globally. Neuron 72:3-5 |
| Dani, Vardhan S; Nelson, Sacha B (2009) Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome. J Neurosci 29:11263-70 |
| Taneja, Praveen; Ogier, Michael; Brooks-Harris, Gabriel et al. (2009) Pathophysiology of locus ceruleus neurons in a mouse model of Rett syndrome. J Neurosci 29:12187-95 |
