Rett Syndrome (RTT, MIM 312750) is an X-linked neuro-developmental condition characterized by a variety of clinical features, most notably loss of hand use and language between 6-18 months of life. Furthermore, affected individuals have prominent hand stereotypes, growth failure, cognitive impairment, autonomic dysfunction and seizures. RTT is caused by mutations in the gene encoding Methyl-CpG Binding Protein 2 (MECP2). An animal model generated in the laboratory of Dr. Zoghbi recapitulates many of the clinical features of RTT and thus is a useful disease model. Importantly, many of the movement abnormalities seen in the human disease are present in the animal model. This proposal is based on the hypothesis that specific clinical features in RTT are attributable to MeCP2 dysfunction within specific neuron populations. Specifically, MeCP2 dysfunction within the nigrostriatal dopaminergic system is the cause of the movement abnormalities in the disease. Therefore, this proposal seeks to explore the dopaminergic system in an animal model of RTT.
The Specific Aims of this grant are to: 1) Characterize the dopaminergic system in RTT mice by studying the neurochemical composition and behavioral response of RTT mice to pharmacological challenge; 2) Determine the consequence of loss of MeCP2 function exclusively in the dopaminergic system; 3) Analyze gene expression changes within pre- and post-synaptic dopamine neurons in the RTT mouse model. These studies will explore the dysfunction of the dopamine system in RTT and will illuminate possible therapeutic strategies for the movement abnormalities found in RTT syndrome. Furthermore, they will shed light on the genetic mechanisms generating movement disorders in general. This insight may pave the way for future therapeutic strategies for other movement disorders such as: Parkinson's disease or Huntington's disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS052240-04
Application #
7394996
Study Section
NST-2 Subcommittee (NST)
Program Officer
Mamounas, Laura
Project Start
2005-07-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$167,988
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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McCauley, Mark D; Wang, Tiannan; Mike, Elise et al. (2011) Pathogenesis of lethal cardiac arrhythmias in Mecp2 mutant mice: implication for therapy in Rett syndrome. Sci Transl Med 3:113ra125
Ward, Christopher S; Arvide, E Melissa; Huang, Teng-Wei et al. (2011) MeCP2 is critical within HoxB1-derived tissues of mice for normal lifespan. J Neurosci 31:10359-70
Chao, Hsiao-Tuan; Chen, Hongmei; Samaco, Rodney C et al. (2010) Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468:263-9
Samaco, Rodney C; Mandel-Brehm, Caleigh; Chao, Hsiao-Tuan et al. (2009) Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities. Proc Natl Acad Sci U S A 106:21966-71
Neul, J L; Fang, P; Barrish, J et al. (2008) Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology 70:1313-21
Samaco, Rodney C; Fryer, John D; Ren, Jun et al. (2008) A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome. Hum Mol Genet 17:1718-27
Fyffe, Sharyl L; Neul, Jeff L; Samaco, Rodney C et al. (2008) Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron 59:947-58