Rett syndrome (RTT) is a complex Autism Spectrum Disorder (ASD) that is caused by mutations in the MECP2 gene and affects approximately 1 in 10,000 live female births worldwide. In addition to cognitive, motor and behavioral deficits, one of the most physically debilitating consequences of RTT is severe disruption in the control of breathing, and up to 25% of RTT patients may die prematurely of cardiorespiratory complications. Currently, there are no treatments available for breathing disorders, or any other neurologic deficits in RTT. Our understanding of neural mechanisms that underlie respiratory dysfunction in RTT is hampered by the fact that we still know little about how loss of MECP2 affects neuronal and/or synaptic function in specific brainstem respiratory circuits. Therefore, the proposed research takes a multidisciplinary approach to define how genetic loss of MECP2 disrupts respiratory control, focusing on modulation of excitatory-inhibitory balance in key respiratory reflex pathways in the brainstem using a well-defined mouse model of the disease. Electrophysiological methods will be used in brainstem slices in vitro to test the hypothesis that increased excitability at primary afferent synapses regulating reflex responses to hypoxia and lung inflation contributes to respiratory circuit dysfunction in RTT and to define underlying mechanisms. We will also examine how deficits in Brain Derived Neurotrophic Factor (BDNF), a key neuronal signaling molecule whose expression is severely decreased in RTT, contribute to synaptic dysfunction, as well as the ability of molecules that enhance BDNF signaling to restore normal function in RTT mice in vitro and in vivo. In addition, we will use Fos immunostaining to map sites throughout the brainstem respiratory network at which neuronal and/or synaptic function is disrupted in vivo. Finally, we will examine how a common polymorphism in the human BDNF gene, Val66Met-BDNF, influences the severity of respiratory symptoms and the therapeutic response to BDNF- targeted therapies in mice. The proposed research aims to define mechanisms that underlie respiratory dysfunction in RTT using innovative experimental approaches and mouse models. By focusing on synaptic excitability, and BDNF-mediated signaling in particular, it is hoped these studies will foster development of new therapeutic strategies for breathing disorders in RTT. Moreover, it is hoped that insights obtained from analysis of circuit dysfunction in RTT will be broadly applicable to ASDs as a whole.

Public Health Relevance

The proposed research seeks to define mechanisms that underlie breathing disorders in Rett syndrome (RTT), a devastating Autism Spectrum Disorder affecting approximately 1 in 10,000 female births worldwide. RTT patients suffer from uncontrollable periods of hyperventilation and breath-holding and up to 25% die prematurely of cardiorespiratory complications. The proposed studies will use mouse models of RTT to identify defects in nerve cell function that cause abnormal breathing in this disease and to develop potential new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS057398-05
Application #
8184609
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Mamounas, Laura
Project Start
2007-04-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$386,867
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
Katz, David M; Bird, Adrian; Coenraads, Monica et al. (2016) Rett Syndrome: Crossing the Threshold to Clinical Translation. Trends Neurosci 39:100-113
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
Dhingra, Rishi R; Zhu, Yenan; Jacono, Frank J et al. (2013) Decreased Hering-Breuer input-output entrainment in a mouse model of Rett syndrome. Front Neural Circuits 7:42
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
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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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