A role for glia in the progression of Rett syndrome

摘要

Rett syndrome (RTT) is an X-chromosome-linked autism spectrum disorder caused by loss of function of the transcription factor methyl CpG-binding protein 2 (MeCP2). Although MeCP2 is expressed in most tissues, loss of MeCP2 results primarily in neurological symptoms^,,. Earlier studies propelled the idea that RTT is due exclusively to loss of MeCP2 function in neurons^,-. While defective neurons clearly underlie the aberrant behaviors, we and others showed recently that the loss of MeCP2 from glia negatively influences neurons in a non-cell autonomous fashion^-. Here, we show that in globally MeCP2-deficient mice, re-expression of MeCP2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged lifespan compared to globally null mice. Furthermore, restoration of MeCP2 in the mutant astrocytes exerted a non-cell-autonomous positive effect on mutant neurons in vivo, restoring normal dendritic morphology and increasing levels of the excitatory glutamate transporter (VGlut1). Our study shows that glia, like neurons, are integral components of the neuropathology of RTT, and supports targeting glia as a strategy for improving the associated symptoms.