Growing evidence indicates that neuronal circuit dysfunction may underlie autism behaviors, although the nature of this impairment and how it leads to autism is still unclear. Despite the fact that neuronal circuit regulation takes place at the synapses — the sites of communication between neurons — very few studies have focused on synaptic proteins and their modification.
Rett syndrome, the most common form of mental retardation in girls, is caused by mutations in the MeCP2 gene, which has a critical role in regulating the expression of synaptic proteins. Michela Fagiolini and her colleagues at Children’s Hospital Boston have identified a clear abnormality in the visual cortex in mouse models of Rett syndrome, which corresponds to the progressive regression of visual acuity with the onset of Rett behavioral symptoms. Remarkably, the visual defect can be successfully rescued by selective manipulation of synaptic NMDA receptors, even in the absence of MeCP2. This strongly suggests that Rett symptoms may be treated through mechanisms that normally control activity-dependent changes in the cortex.
Fagiolini and her colleague Judith Steen are using breakthrough discoveries in Rett syndrome to investigate treatments for autism. Using cutting-edge proteomics (quantitative protein analysis) tools developed in the Steen laboratory, they plan to measure the composition and changes in NMDA receptor subunits in MeCP2-deficient mice. They then aim to test whether NMDA receptor subunits represent therapeutic targets for the recovery of cortical function in individuals with autism.
