Rett Syndrome is a form of severe mental retardation. The overall goal of this proposal is to define the neurodevelopmental defects in Rett Syndrome using the olfactory system as a model. Although Rett Syndrome has a genetic basis, the neuronal defect(s) in Rett Syndrome are unknown. As with many neurological disorders, our understanding of Rett Syndrome is hindered by the inaccessibility of brain tissue during the period of disease progression. Olfactory receptor neurons (ORNs) are continually replaced during life from a population of basal cells, recapitulating their developmental program. They are accessible to low-risk biopsies. Thus, ORNs provide a unique model for Rett Syndrome. Our results obtained from nasal biopsies of Rett Syndrome patients and age-matched controls confirm the feasibility and usefulness of this multidisciplinary approach. We hypothesize that ORN differentiation is arrested by a non-cell-autonomous mechanism that disrupts dendritic development and initiates apoptosis.
Aim 1 will analyze olfactory biopsies of Rett and age-matched controls by immunohistochemistry and electron microscopy using stage-specific markers to determine the phenotype and the developmental stage of arrested ORNs. TUNEL staining and PCNA are used to evaluate cell death and compensatory neurogenesis. The expression and distribution of proteins whose involvement in pathogenesis is suggested by high density arrays is studied. The specificity of the morphological changes seen in the olfactory epithelium of Rett is determined by comparisons to biopsies from Fragile X, Down's Syndrome, and autism.
Aim 2 will evaluate the olfactory bulb, the only target of ORNs. The simple circuitry and ongoing synaptogenesis in the olfactory bulb make it an excellent model to determine the consequences of this arrest on the morphology of mitral cells axons and dendrites, and their connectivity to ORNs. We will use immunocytochemistry, retrograde labeling techniques, and tyrosine hydroxylase staining.
Aim 3 will assess the functional consequences of the defects seen in ORNs and the bulb by odorant-stimulated functional MRI.
Aim 4 will exploit our extensive experience with ORN culture and modeling of physiologically-relevant factors required for ORN survival. We will investigate the ability of in vitro modulations to ameliorate ORN phenotype in cultures isolated from Rett biopsies compared to age-matched controls. These experiments will test our hypothesis that Rett is caused by a non-cell-autonomous mechanism from which ORNs can be rescued in vitro. Thus, understanding the primary and secondary defects in Rett Syndrome will provide insight into an important aspect of post-natal brain developmental plasticity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041079-04
Application #
6659866
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Mamounas, Laura
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$335,566
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kim, So Yeun; Mammen, Alex; Yoo, Seung-Jun et al. (2015) Phosphoinositide and Erk signaling pathways mediate activity-driven rodent olfactory sensory neuronal survival and stress mitigation. J Neurochem 134:486-98
Degano, Alicia L; Park, Min Jung; Penati, Judith et al. (2014) MeCP2 is required for activity-dependent refinement of olfactory circuits. Mol Cell Neurosci 59:63-75
McFadden, Joseph W; Aja, Susan; Li, Qun et al. (2014) Increasing fatty acid oxidation remodels the hypothalamic neurometabolome to mitigate stress and inflammation. PLoS One 9:e115642
Park, Min Jung; Aja, Susan; Li, Qun et al. (2014) Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice. PLoS One 9:e109527
Palmer, A M; Degano, A L; Park, M J et al. (2012) Normal mitral cell dendritic development in the setting of Mecp2 mutation. Neuroscience 202:108-16
Zhu, Jing; Aja, Susan; Kim, Eun-Kyoung et al. (2012) Physiological oxygen level is critical for modeling neuronal metabolism in vitro. J Neurosci Res 90:422-34
Kuhajda, Francis P; Aja, Susan; Tu, Yajun et al. (2011) Pharmacological glycerol-3-phosphate acyltransferase inhibition decreases food intake and adiposity and increases insulin sensitivity in diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 301:R116-30
Degano, Alicia L; Pasterkamp, R Jeroen; Ronnett, Gabriele V (2009) MeCP2 deficiency disrupts axonal guidance, fasciculation, and targeting by altering Semaphorin 3F function. Mol Cell Neurosci 42:243-54
El Meskini, Rajaa; Crabtree, Kelli L; Cline, Laura B et al. (2007) ATP7A (Menkes protein) functions in axonal targeting and synaptogenesis. Mol Cell Neurosci 34:409-21
Ronnett, Gabriele V; Leopold, Donald; Cai, Xiaohe et al. (2003) Olfactory biopsies demonstrate a defect in neuronal development in Rett's syndrome. Ann Neurol 54:206-18