Disrupted Homeostatic Synaptic Plasticity as a Potential Cause of Cortical Dysfunction in Rett Syndrome.

摘要

Loss of function mutations in the X-linked gene methyl-CpG binding protein 2 (MePC2) cause Rett syndrome and have been implicated in other forms of mental retardation and autism. Affected females develop normally for 6-18 months and then develop symptoms including seizures and the loss of voluntary movements and language; patients eventually develop severe motor and cognitive abnormalities. Despite much effort it remains unclear how a loss of MeCP2 function generates the neurological deficits of Rett. Previous work has shown that in a mouse model of Rett there is an imbalance of synaptic excitation and inhibition within cortical networks. This balance is thought to be maintained by homeostatic synaptic plasticity mechanisms, suggesting that in Rett one underlying cause of cortical dysfunction is disrupted homeostatic synaptic plasticity.;The major aim of this thesis was to characterize the role of MeCP2 in one form of homeostatic synaptic plasticity, synaptic scaling. In synaptic scaling neurons bi-directionally regulate synaptic weights in response to chronic changes in network activity in the correct direction to stabilize firing rates. Here I show that knockdown of MeCP2 with short hairpin RNAs (shRNAs) in dissociated rat cortical neurons blocks the expression of synaptic scaling up. Acute and cell-autonomous loss of MeCP2 reduced excitatory synapse number suggesting that the reduction of excitatory synapses consistently seen in both mouse models and post mortem Rett brains is a primary defect due to a cell-autonomous loss of MeCP2. Finally, I present preliminary data suggesting that inhibiting DNA methyltransferases, the enzymes responsible for DNA methylation, blocks synaptic scaling up, suggesting that MeCP2 regulation of synaptic scaling up involves MeCP2 binding to methylated DNA. These data reveal the involvement of MeCP2 in synaptic scaling, a form of homeostatic synaptic plasticity suggested to be necessary for proper development and function of neural networks, and suggest that some of the neurological defects of Rett arise from a disruption of homeostatic plasticity.