Curr Biol. 2006 Apr 4;16(7):710-6.
MeCP2-dependent transcriptional repression regulates excitatory neurotransmission
Nelson ED, Kavalali ET, Monteggia LM.
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas,TX
Abstract
Mutations in the transcriptional repressor, methyl-CpG binding protein 2 (MeCP2), result in a neurodevelopmental disorder called Rett Syndrome (RTT). Based on the neurological phenotypes observed in Rett patients, we examined the potential role of MeCP2 in synaptic function. We compared elementary properties of synaptic transmission between cultured hippocampal neurons from MeCP2 knockout and wild-type littermate control mice and found a decrease in the frequency of spontaneous excitatory synaptic transmission (mEPSCs) in neurons lacking MeCP2. We also detected a significant increase in the rate of short-term synaptic depression. To explore whether these functional effects can be attributed to MeCP2's role as a transcriptional silencer, we treated cultures with a drug that impairs histone deacetylation and examined spontaneous synaptic transmission. Treatment with this compound induced a similar decrease in mEPSC frequency in wild-type control cultures, but this decrease was occluded in MeCP2-deficient neurons. Interestingly, neither the loss of MeCP2 nor the drug treatment resulted in changes in mIPSC properties. Finally, by means of a lentivirus expressing Cre recombinase, we show that loss of MeCP2 function after neurodevelopment and synaptogenesis was sufficient to mimic the decrease in mEPSC frequency seen in constitutive MeCP2 KO neurons. Taken together, these results suggest a role for MeCP2 in control of excitatory presynaptic function through regulation of gene expression.
Lay Summary
By placing electrodes within an isolated slice of brain tissue, scientists are able to understand the electrical communication that occurs between different populations of living neurons. In this study, similar investigations were performed in individual brain cells in culture, dissociated from their whole brain environment. Here, brain cells lacking MeCP2 were isolated and communication between cells was examined. While supporting earlier findings, a few novel findings were revealed. Most notably, normal brain cells were exposed to either a drug that blocks MeCP2 function, or genetic manipulation to interrupt the expression of the MeCP2 gene. In both conditions, the resulting changes in synaptic behaviour mimicked those behaviours found in cells lacking MeCP2. Thus, these data further provide evidence for a key role for MeCP2 in controlling synaptic plasticity. This information is important as it aids in delineating the functional abnormalities that lead to the wide array of brain deficits observed in Rett patients