The major objective of this proposal is to further delineate the role of MeCP2, the gene linked to Rett Syndrome (RTT), in excitatory neurotransmission through its function as a transcriptional repressor. We have recently shown that the loss of MeCP2 in neurons contributes to alterations in exicitatory, but not inhibitory, synaptic transmission. We also demonstrated that these deficits in excitatory transmission, a component of short term plasticity, appear due to MeCP2's role as a transcriptional repressor. Conversely we have recently found that overexpression of MeCP2 results in alterations in excitatory synaptic transmission and synaptic depression opposite to those obtained following the loss of MeCP2. This is important because if MeCP2 is a bona fide regulator of synaptic function then we would expect bidirectional changes in MeCP2 to result in reciprocal alterations in neurotransmission. The proposed studies will complement and extend our previous work by addressing three specific aims using molecular, cellular and electrophysiological methods. We will first, further characterize the loss of MeCP2 in short term plasticity to more fully discern its endogenous role in neuronal function. Second, we will characterize the overexpression of MeCP2 in short term plasticity to examine how alterations in MeCP2 expression effects synaptic transmission. This is important since recent studies have shown that duplication of the MeCP2 gene may underlie certain forms of mental retardation and progressive neurological symptoms. Lastly, we will elucidate the role of histone deacetylases (HDACs) 1 and 2, key repressors of gene repression that are part of a multiprotein complex with MeCP2 in regulating gene expression, on synaptic transmission. Our hypothesis is that alterations in MeCP2 expression contribute to effects on synaptic function. The studies proposed in this application will extend our original hypothesis by further characterizing how alterations in the expression of MeCP2 contributes to deficits in neurotransmission as well as how the HDAC components of the MeCP2 complex may be involved in these processes. This information is important because it will start to provide a framework in which to explore how synaptic alterations may underlie aspects of RTT.
The experiments proposed in this project represent a comprehensive effort to address the role of MeCP2, the gene linked to Rett Syndrome, in excitatory neurotransmission through its function as a transcriptional repressor. Currently, a thorough analysis of the role of MeCP2 in short-term synaptic plasticity in central synapses is lacking. In this project, we will examine via complementary approaches how the loss of MeCP2 or the overexpression of MeCP2 contributes to alterations in synaptic transmission. We will also elucidate the role of histone deacetylases (HDACs) 1 and 2, key repressors of gene repression that are part of a multiprotein complex with MeCP2 in regulating gene expression, on synaptic transmission. Information attained from these studies will provide new insight into the synaptic mechanisms that may be affected in Rett Syndrome as well as related disorders that involve alterations in MeCP2 expression.
| Monteggia, Lisa M; Lin, Pei-Yi; Adachi, Megumi et al. (2018) Behavioral Analysis of SNAP-25 and Synaptobrevin-2 Haploinsufficiency in Mice. Neuroscience : |
| Horvath, Patricia M; Kavalali, Ege T; Monteggia, Lisa M (2017) CRISPR/Cas9 system-mediated impairment of synaptobrevin/VAMP function in postmitotic hippocampal neurons. J Neurosci Methods 278:57-64 |
| Mahgoub, Melissa; Adachi, Megumi; Suzuki, Kanzo et al. (2016) MeCP2 and histone deacetylases 1 and 2 in dorsal striatum collectively suppress repetitive behaviors. Nat Neurosci 19:1506-1512 |
| Morris, Michael J; Na, Elisa S; Autry, Anita E et al. (2016) Impact of DNMT1 and DNMT3a forebrain knockout on depressive- and anxiety like behavior in mice. Neurobiol Learn Mem 135:139-145 |
| Adachi, Megumi; Lin, Pei-Yi; Pranav, Heena et al. (2016) Postnatal Loss of Mef2c Results in Dissociation of Effects on Synapse Number and Learning and Memory. Biol Psychiatry 80:140-148 |
| Na, Elisa S; Morris, Michael J; Nelson, Erika D et al. (2014) GABAA receptor antagonism ameliorates behavioral and synaptic impairments associated with MeCP2 overexpression. Neuropsychopharmacology 39:1946-54 |
| Morris, Michael J; Adachi, Megumi; Na, Elisa S et al. (2014) Selective role for DNMT3a in learning and memory. Neurobiol Learn Mem 115:30-7 |
| Adachi, Megumi; Monteggia, Lisa M (2014) Decoding transcriptional repressor complexes in the adult central nervous system. Neuropharmacology 80:45-52 |
| Morris, Michael J; Mahgoub, Melissa; Na, Elisa S et al. (2013) Loss of histone deacetylase 2 improves working memory and accelerates extinction learning. J Neurosci 33:6401-11 |
| Mahgoub, Melissa; Monteggia, Lisa M (2013) Epigenetics and psychiatry. Neurotherapeutics 10:734-41 |
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