{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/628"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/628","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"MeCP2 and the Epigenetic Regulation of Excitatory Synaptic Transmission","abstract":"Accurate regulation of gene expression is critical for normal brain function. Many human neurodevelopmental and neurodegenerative disorders are associated with mutations in genes important for controlling transcription. Mutations in one such gene, the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2), lead to a form of mental retardation called Rett Syndrome (RTT). Though the MeCP2 protein is expressed ubiquitously, symptoms of RTT patients are primarily neurological, which include reduced mental capacity, autistic-like behavior and autonomic dysfunction. In addition, a mouse model with reduced MeCP2 expression specifically in postnatal, forebrain neurons recapitulates many of the phenotypes seen in human patients. These findings, among others, lead to interest in MeCP2's function in the brain. Our research has focused on the transcriptional repression activity of MeCP2 and its role in the regulation of synapse function. Using mainly electrophysiological techniques, we found that the loss of MeCP2 in hippocampal neurons results in deficits in both spontaneous and evoked excitatory synaptic transmission. Using pharmacological manipulations, we were able to attribute these deficits to the loss of transcriptional repression by MeCP2. By utilizing a conditional knockout approach, we found that these effects were not due to the loss of MeCP2 during neurodevelopment and that they were primarily due to a deficiency in presynaptic vesicle release. We further extended these findings by looking at two mechanisms for controlling the repression of gene expression, DNA methylation and histone deacetylation, both of which are important for MeCP2's function as a transcriptional repressor. Using inhibitors of DNA methyltransferases, we discovered that synaptic activity-dependent decreases in DNA methylation occur in post-mitotic neurons, and that these changes in DNA methylation can regulate spontaneous synaptic transmission. We were also able to rescue the MeCP2-dependent decrease in spontaneous activity by treating neurons with the methyl donor, S-adenosyl-L-methionine. Finally, we addressed the role of histone deacetylation in synapse function by conditionally deleting histone deacetylases (HDACs) 1 and 2 from mature hippocampal neurons. HDAC1 and 2 are present in the transcriptional repressor complex containing MeCP2. After acute knockdown of HDAC1 or HDAC2, we found deficits in excitatory synaptic transmission that mimicked the defects seen after the constitutive loss of MeCP2. In summary, we have discovered a role for the transcriptional repressor, MeCP2, and two components of its repressor complex, DNA methylation and HDACs, in the control of excitatory synaptic transmission between hippocampal neurons.","abstract_html":"Accurate regulation of gene expression is critical for normal brain function. Many human neurodevelopmental and neurodegenerative disorders are associated with mutations in genes important for controlling transcription. Mutations in one such gene, the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2), lead to a form of mental retardation called Rett Syndrome (RTT). Though the MeCP2 protein is expressed ubiquitously, symptoms of RTT patients are primarily neurological, which include reduced mental capacity, autistic-like behavior and autonomic dysfunction. In addition, a mouse model with reduced MeCP2 expression specifically in postnatal, forebrain neurons recapitulates many of the phenotypes seen in human patients. These findings, among others, lead to interest in MeCP2's function in the brain. Our research has focused on the transcriptional repression activity of MeCP2 and its role in the regulation of synapse function. Using mainly electrophysiological techniques, we found that the loss of MeCP2 in hippocampal neurons results in deficits in both spontaneous and evoked excitatory synaptic transmission. Using pharmacological manipulations, we were able to attribute these deficits to the loss of transcriptional repression by MeCP2. By utilizing a conditional knockout approach, we found that these effects were not due to the loss of MeCP2 during neurodevelopment and that they were primarily due to a deficiency in presynaptic vesicle release. We further extended these findings by looking at two mechanisms for controlling the repression of gene expression, DNA methylation and histone deacetylation, both of which are important for MeCP2's function as a transcriptional repressor. Using inhibitors of DNA methyltransferases, we discovered that synaptic activity-dependent decreases in DNA methylation occur in post-mitotic neurons, and that these changes in DNA methylation can regulate spontaneous synaptic transmission. We were also able to rescue the MeCP2-dependent decrease in spontaneous activity by treating neurons with the methyl donor, S-adenosyl-L-methionine. Finally, we addressed the role of histone deacetylation in synapse function by conditionally deleting histone deacetylases (HDACs) 1 and 2 from mature hippocampal neurons. HDAC1 and 2 are present in the transcriptional repressor complex containing MeCP2. After acute knockdown of HDAC1 or HDAC2, we found deficits in excitatory synaptic transmission that mimicked the defects seen after the constitutive loss of MeCP2. In summary, we have discovered a role for the transcriptional repressor, MeCP2, and two components of its repressor complex, DNA methylation and HDACs, in the control of excitatory synaptic transmission between hippocampal neurons.","abstract_has_math":false,"creators":["Nelson, Erika Dawn"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Monteggia, Lisa","Bezprozvanny, Ilya","Kavalali, Ege T.","Lin, Weichun"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-07-12T18:38:21Z","date_published":"2010-07-12T18:38:21Z","updated_at":"2026-07-24T05:52:38Z","subjects":["Synaptic Transmission","Methyl-CpG-Binding Protein 2","Repressor Proteins"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["756838115"],"render_values":[{"text":"756838115","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/628","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Monteggia, Lisa","Bezprozvanny, Ilya","Kavalali, Ege T.","Lin, Weichun"]},{"key":"dc:creator","label":"Author","values":["Nelson, Erika Dawn"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-07-12T18:38:21Z","2007-08-08"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","Text","dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Synaptic Transmission","Methyl-CpG-Binding Protein 2","Repressor Proteins"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/628","756838115"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Accurate regulation of gene expression is critical for normal brain function. Many human neurodevelopmental and neurodegenerative disorders are associated with mutations in genes important for controlling transcription. Mutations in one such gene, the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2), lead to a form of mental retardation called Rett Syndrome (RTT). Though the MeCP2 protein is expressed ubiquitously, symptoms of RTT patients are primarily neurological, which include reduced mental capacity, autistic-like behavior and autonomic dysfunction. In addition, a mouse model with reduced MeCP2 expression specifically in postnatal, forebrain neurons recapitulates many of the phenotypes seen in human patients. These findings, among others, lead to interest in MeCP2's function in the brain. Our research has focused on the transcriptional repression activity of MeCP2 and its role in the regulation of synapse function. Using mainly electrophysiological techniques, we found that the loss of MeCP2 in hippocampal neurons results in deficits in both spontaneous and evoked excitatory synaptic transmission. Using pharmacological manipulations, we were able to attribute these deficits to the loss of transcriptional repression by MeCP2. By utilizing a conditional knockout approach, we found that these effects were not due to the loss of MeCP2 during neurodevelopment and that they were primarily due to a deficiency in presynaptic vesicle release. We further extended these findings by looking at two mechanisms for controlling the repression of gene expression, DNA methylation and histone deacetylation, both of which are important for MeCP2's function as a transcriptional repressor. Using inhibitors of DNA methyltransferases, we discovered that synaptic activity-dependent decreases in DNA methylation occur in post-mitotic neurons, and that these changes in DNA methylation can regulate spontaneous synaptic transmission. We were also able to rescue the MeCP2-dependent decrease in spontaneous activity by treating neurons with the methyl donor, S-adenosyl-L-methionine. Finally, we addressed the role of histone deacetylation in synapse function by conditionally deleting histone deacetylases (HDACs) 1 and 2 from mature hippocampal neurons. HDAC1 and 2 are present in the transcriptional repressor complex containing MeCP2. After acute knockdown of HDAC1 or HDAC2, we found deficits in excitatory synaptic transmission that mimicked the defects seen after the constitutive loss of MeCP2. In summary, we have discovered a role for the transcriptional repressor, MeCP2, and two components of its repressor complex, DNA methylation and HDACs, in the control of excitatory synaptic transmission between hippocampal neurons."]},{"key":"dc:format","label":"Dc Format","values":["Electronic","application/pdf","born digital"]},{"key":"dc:title","label":"Title","values":["MeCP2 and the Epigenetic Regulation of Excitatory Synaptic Transmission"]}]}],"canonical_facts":{"dc:contributor":["Monteggia, Lisa","Bezprozvanny, Ilya","Kavalali, Ege T.","Lin, Weichun"],"dc:creator":["Nelson, Erika Dawn"],"dc:date":["2010-07-12T18:38:21Z","2007-08-08"],"dc:description":["Accurate regulation of gene expression is critical for normal brain function. Many human neurodevelopmental and neurodegenerative disorders are associated with mutations in genes important for controlling transcription. Mutations in one such gene, the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2), lead to a form of mental retardation called Rett Syndrome (RTT). Though the MeCP2 protein is expressed ubiquitously, symptoms of RTT patients are primarily neurological, which include reduced mental capacity, autistic-like behavior and autonomic dysfunction. In addition, a mouse model with reduced MeCP2 expression specifically in postnatal, forebrain neurons recapitulates many of the phenotypes seen in human patients. These findings, among others, lead to interest in MeCP2's function in the brain. Our research has focused on the transcriptional repression activity of MeCP2 and its role in the regulation of synapse function. Using mainly electrophysiological techniques, we found that the loss of MeCP2 in hippocampal neurons results in deficits in both spontaneous and evoked excitatory synaptic transmission. Using pharmacological manipulations, we were able to attribute these deficits to the loss of transcriptional repression by MeCP2. By utilizing a conditional knockout approach, we found that these effects were not due to the loss of MeCP2 during neurodevelopment and that they were primarily due to a deficiency in presynaptic vesicle release. We further extended these findings by looking at two mechanisms for controlling the repression of gene expression, DNA methylation and histone deacetylation, both of which are important for MeCP2's function as a transcriptional repressor. Using inhibitors of DNA methyltransferases, we discovered that synaptic activity-dependent decreases in DNA methylation occur in post-mitotic neurons, and that these changes in DNA methylation can regulate spontaneous synaptic transmission. We were also able to rescue the MeCP2-dependent decrease in spontaneous activity by treating neurons with the methyl donor, S-adenosyl-L-methionine. Finally, we addressed the role of histone deacetylation in synapse function by conditionally deleting histone deacetylases (HDACs) 1 and 2 from mature hippocampal neurons. HDAC1 and 2 are present in the transcriptional repressor complex containing MeCP2. After acute knockdown of HDAC1 or HDAC2, we found deficits in excitatory synaptic transmission that mimicked the defects seen after the constitutive loss of MeCP2. In summary, we have discovered a role for the transcriptional repressor, MeCP2, and two components of its repressor complex, DNA methylation and HDACs, in the control of excitatory synaptic transmission between hippocampal neurons."],"dc:format":["Electronic","application/pdf","born digital"],"dc:identifier":["https://hdl.handle.net/2152.5/628","756838115"],"dc:language":["en"],"dc:subject":["Synaptic Transmission","Methyl-CpG-Binding Protein 2","Repressor Proteins"],"dc:title":["MeCP2 and the Epigenetic Regulation of Excitatory Synaptic Transmission"],"dc:type":["Thesis","Text","dissertation"]},"updated_at":"2026-07-24T05:52:38Z"}