The aim of the proposed research is to define how genetic loss of MeCP2, the gene responsible for Rett Syndrome (Rett), disrupts Brain Derived Neurotrophic Factor (BDNF) signaling in autonomic reflex pathways in the brainstem nucleus tractus solitarius (nTS). nTS is the principal site at which visceral sensory input is integrated in the brainstem and defects in nTS function have been proposed to underlie autonomic dysfunctions in Rett. Normally, visceral sensory neurons, located in the nodose-petrosal cranial sensory ganglia (NPG), synthesize and release high levels of BDNF, a putative transcriptional target of MeCP2. However, we recently found that expression and secretion of BDNF are severely impaired in NPG neurons of MeCP2 null mice. In particular, levels of BDNF protein are markedly depressed in mutant NPG neurons compared to wildtype cells, although levels of BDNF mRNA are normal. In addition, mutant cells exhibit abnormally high levels of constitutive BDNF release. As a result, we hypothesize that transynaptic BDNF signaling by visceral sensory neurons in nTS is disrupted by genetic loss of MeCP2. Moreover, recent studies in our laboratory indicate that BDNF can potently modulate the excitability of second order relay neurons in nTS and that this modulation is impaired in MeCP2 null mice. On the basis of these findings we hypothesize that dysregulation of BDNF signaling by NPG neurons contributes to the life-threatening autonomic dysfunctions associated with Rett. However, almost nothing is known about mechanisms of BDNF signaling in nTS in general and the role of MeCP2 in particular. The proposed studies are designed, therefore, to elucidate 1) basic mechanisms of synaptic modulation by BDNF in nTS, using brainstem slice preparations, 2) how loss of MeCP2 function alters BDNF dependent signaling by visceral sensory neurons and synaptic transmission in nTS and 3) the role of BDNF in nTS mediated autonomic reflexes in vivo. In addition, we have recently found that the BDNF deficit in MeCP2 null NPG neurons is reversible in vitro. Therefore, the proposed studies are also designed to develop potential strategies for increasing or restoring normal levels of BDNF expression in MeCP2 null mutants in vivo. By elucidating the roles of BDNF and MeCP2 in autonomic reflex pathways, the proposed research aims to shed light on cellular and molecular mechanisms relevant to understanding and improved management of Rett Syndrome and other disorders of autonomic homeostasis. In particular, it is hoped that defining how MeCP2 disrupts BDNF dependent signaling by visceral sensory neurons will lead to identification of new molecular targets for drug development aimed at improving autonomic function in Rett patients.. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057398-02
Application #
7386688
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Mamounas, Laura
Project Start
2007-04-01
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$367,735
Indirect Cost
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Sceniak, Michael P; Lang, Min; Enomoto, Addison C et al. (2016) Mechanisms of Functional Hypoconnectivity in the Medial Prefrontal Cortex of Mecp2 Null Mice. Cereb Cortex 26:1938-1956
Kron, Miriam; Lang, Min; Adams, Ian T et al. (2014) A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome. Dis Model Mech 7:1047-55
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Katz, David M; Berger-Sweeney, Joanne E; Eubanks, James H et al. (2012) Preclinical research in Rett syndrome: setting the foundation for translational success. Dis Model Mech 5:733-45
Kron, Miriam; Howell, C James; Adams, Ian T et al. (2012) Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment. J Neurosci 32:13860-72
Schmid, Danielle A; Yang, Tao; Ogier, Michael et al. (2012) A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome. J Neurosci 32:1803-10
Clark, Catharine G; Hasser, Eileen M; Kunze, Diana L et al. (2011) Endogenous brain-derived neurotrophic factor in the nucleus tractus solitarius tonically regulates synaptic and autonomic function. J Neurosci 31:12318-29
Shepherd, Gordon M G; Katz, David M (2011) Synaptic microcircuit dysfunction in genetic models of neurodevelopmental disorders: focus on Mecp2 and Met. Curr Opin Neurobiol 21:827-33
Kline, David D; Ogier, Michael; Kunze, Diana L et al. (2010) Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in Mecp2-null mice. J Neurosci 30:5303-10

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