Over the past ~5 years, we have examined the role of MeCP2 in neurotransmission as a transcriptional factor impacting gene expression. Our data has revealed that MeCP2 is a bona fide regulator of synaptic function with bidirectional changes in MeCP2 resulting in reciprocal alterations in neurotransmission. We have also shown alterations in MeCP2 expression in mice result in several behavioral phenotypes as well as deficits in specific measures of synaptic plasticity further implicating MeCP2 as a key mediator of synaptic processes. A rather surprising finding in the field of depression has been the demonstration that scopolamine, a muscarinic acetylcholine receptor antagonist, has rapid and long-lasting antidepressant responses in depressed individuals. We have started to investigate the mechanism of the antidepressant action of scopolamine, and have found it is dependent on MeCP2 expression as these effects are lost in Mecp2 knockout mice. Our findings also suggest that the antidepressant effects of scopolamine are dependent on MeCP2-dependent transcriptional mechanisms resulting in increased BDNF expression that is important for the behavioral effects. Our preliminary data further suggests that scopolamine triggers MeCP2 phosphorylation at Serine 421 (pMeCP2), which has been shown to regulate BDNF expression. In initial experiments, we find that scopolamine acts via blockade of the muscarinic M1 receptor to trigger pMeCP2. The objective of this grant is to explore the novel hypothesis that MeCP2- dependent transcriptional mechanisms underlie the fast acting antidepressant effects of scopolamine. We will use state of the art behavioral as well as cellular and biochemical approaches to examine our hypothesis. Collectively, these studies will contribute to a better understanding of mechanisms underlying fast-acting antidepressant responses as well as provide novel insight into MeCP2 regulation as a therapeutic target.

Public Health Relevance

The objective of this grant is to study the role of MeCP2 in mediating antidepressant responses in mice. Based on our preliminary data presented in this application, we will examine the role of MeCP2 in scopolamine-mediated fast-acting antidepressant responses upstream of BDNF. These studies will use molecular, cellular and behavioral approaches to investigate signaling pathways involved in mediating rapid antidepressant responses, in the hopes of developing faster-acting antidepressants.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH081060-07
Application #
8744305
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nadler, Laurie S
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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
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
Na, Elisa S; Nelson, Erika D; Kavalali, Ege T et al. (2013) The impact of MeCP2 loss- or gain-of-function on synaptic plasticity. Neuropsychopharmacology 38:212-9
Morris, Michael J; Monteggia, Lisa M (2013) Unique functional roles for class I and class II histone deacetylases in central nervous system development and function. Int J Dev Neurosci 31:370-81
Akhtar, M Waseem; Kim, Mi-Sung; Adachi, Megumi et al. (2012) In vivo analysis of MEF2 transcription factors in synapse regulation and neuronal survival. PLoS One 7:e34863
Na, Elisa S; Nelson, Erika D; Adachi, Megumi et al. (2012) A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission. J Neurosci 32:3109-17
Autry, Anita E; Monteggia, Lisa M (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64:238-58
Na, Elisa S; Monteggia, Lisa M (2011) The role of MeCP2 in CNS development and function. Horm Behav 59:364-8

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