Re-expression of MeCP2 in early adulthood recovers cortical function in Rett syndrome

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Re-expression of MeCP2 in early adulthood recovers cortical function in Rett syndrome

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Title: Re-expression of MeCP2 in early adulthood recovers cortical function in Rett syndrome
Author: Simon, Alex Joseph
Citation: Simon, Alex Joseph. 2016. Re-expression of MeCP2 in early adulthood recovers cortical function in Rett syndrome. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
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Abstract: Impacting 1 in 10,000 girls, Rett syndrome (RTT) is caused by de novo mutations in the X chromosome gene, MECP2. Girls with RTT initially appear normal and reach developmental milestones in their first 6 months; nevertheless, they soon succumb to a symptomatic regression defined by a loss of motor, cognitive, social, and language skills and the onset of epilepsy. No cure exists.

Remarkably, the re-expression of MeCP2 in adult Mecp2-mutant mice is sufficient to reverse motor and respiratory phenotypes, which provides hope for future interventions in RTT patients. One question that remains unanswered is whether abnormalities in sensory information processing—an essential component of language, emotion and cognition—are amenable to rescue in adulthood, and if so, to what degree. Distinctively, sensory circuits are most amenable to modification in early stages of development, rather than in adulthood.

Using the visual system as a model, we tested whether the lateral geniculate nucleus (LGN) and visual cortex (V1) were sensitive to both the loss and re-expression of MeCP2 in early adulthood. We found that post-natal deletion of MeCP2 disrupted excitatory neuronal function in the cortex, but did not perturb inhibitory interneuron connectivity in V1 nor anatomical wiring of the retinogeniculate synapse. Re-expression of MeCP2 in early adulthood permitted the recovery of pyramidal neuron function and visually evoked potential responses; yet, it failed to fully rescue all pre-existing deficits in cortex.

Although cortical RTT phenotypes were not completely reversed, our results suggest that re-expressing MeCP2 in early adulthood significantly ameliorates the condition and function of abnormally wired cortical circuits. Consequently, with regards to future Rett syndrome therapeutics, we are optimistic about the possibility for some degree of recovery in sensory processing after patients have undergone regression.
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:33840720
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