Research Awards
Ege T. Kavalali, Ph.D.
University of Texas Southwestern Medical Center at Dallas
"A role for MeCP2 in synaptic function"
2-Year Award: $99,880
Research Sponsor: Ford Motor Company
Final Report (November 2005)
In humans, mutations in the gene MeCP2 have been found to result in a neurodevelopmental disorder called Rett Syndrome (RTT). While it is believed that MeCP2 functions as a transcriptional repressor, there is currently no direct link between the loss of function in MeCP2 and the pathogenesis of RTT.
Based on the neurological phenotypes seen in RTT, we hypothesized that MeCP2 plays a role in the maintenance and/or regulation of synaptic transmission between central neurons. To examine this, we carried out a number of electrophysiological and imaging experiments on neurons cultured from hippocampal brain regions of MeCP2 knockout mice. Dissociated hippocampal cultures provide an experimentally amenable system to study the basic properties of synaptic communication between neurons. Using electrophysiological recordings, we found a specific decrease in the frequency of spontaneous excitatory synaptic transmission in neurons lacking MeCP2 compared to wild type controls. We also found that the number of functional synaptic vesicles (membranous organelles that contain neurotransmitters) in MeCP2 knockout neurons were similar to wild type controls. We also examined the dynamic properties of synaptic transmission in the MeCP2 knockout cultures by measuring responses to train stimulation and observed a faster synaptic depression and slower response recovery after synaptic depression in the knockout neurons.
We then investigated whether these functional defects can be ascribed to loss of MeCP2's function as a transcriptional repressor. 24 hour treatment with drugs that impair DNA methylation and histone deacetylation produced similar functional changes in wild type neurons but were blocked in neurons lacking MeCP2 suggesting a role for MeCP2 in the control of neurotransmitter release through the regulation of presynaptic genes.
Thus these results show that basic synaptic abnormalities observed with the loss of MeCP2 are due to MeCP2's role as a transcriptional repressor and not an outcome of aberrant neuronal development. We think this is an important finding that argues against the 'neurodevelopmental' characterization of the disorder and instead suggests that MeCP2 acts as a bona fide regulator of synaptic transmission through its transcriptional repressor activity.
Ege T. Kavalali, Ph.D.University of Texas Southwestern Medical Center at Dallas
"A role for MeCP2 in synaptic function"
2-Year Award: $99,880
Research Sponsor: Ford Motor Company
Final Report (November 2005)
In humans, mutations in the gene MeCP2 have been found to result in a neurodevelopmental disorder called Rett Syndrome (RTT). While it is believed that MeCP2 functions as a transcriptional repressor, there is currently no direct link between the loss of function in MeCP2 and the pathogenesis of RTT.
Based on the neurological phenotypes seen in RTT, we hypothesized that MeCP2 plays a role in the maintenance and/or regulation of synaptic transmission between central neurons. To examine this, we carried out a number of electrophysiological and imaging experiments on neurons cultured from hippocampal brain regions of MeCP2 knockout mice. Dissociated hippocampal cultures provide an experimentally amenable system to study the basic properties of synaptic communication between neurons. Using electrophysiological recordings, we found a specific decrease in the frequency of spontaneous excitatory synaptic transmission in neurons lacking MeCP2 compared to wild type controls. We also found that the number of functional synaptic vesicles (membranous organelles that contain neurotransmitters) in MeCP2 knockout neurons were similar to wild type controls. We also examined the dynamic properties of synaptic transmission in the MeCP2 knockout cultures by measuring responses to train stimulation and observed a faster synaptic depression and slower response recovery after synaptic depression in the knockout neurons.
We then investigated whether these functional defects can be ascribed to loss of MeCP2's function as a transcriptional repressor. 24 hour treatment with drugs that impair DNA methylation and histone deacetylation produced similar functional changes in wild type neurons but were blocked in neurons lacking MeCP2 suggesting a role for MeCP2 in the control of neurotransmitter release through the regulation of presynaptic genes.
Thus these results show that basic synaptic abnormalities observed with the loss of MeCP2 are due to MeCP2's role as a transcriptional repressor and not an outcome of aberrant neuronal development. We think this is an important finding that argues against the 'neurodevelopmental' characterization of the disorder and instead suggests that MeCP2 acts as a bona fide regulator of synaptic transmission through its transcriptional repressor activity.