Neuronal dendritic morphology and intrinsic properties are specialized for their function. Dendritic defects are strongly associated with numerous neurodevelopmental disorders. In this proposal, I endeavor to identify roles of fragile X mental retardation protein (FMRP) in dendritic regulation of auditory neurons. Absence of FMRP results in fragile X syndrome (FXS), the most frequent inherited monogenetic cause of autism, presenting with a constellation of symptoms that include intelligence deficits and sensory dysfunction. I propose to study FMRP regulation during development of very well characterized binaural circuitry in the brainstem and its role in regulation of dendritic morpholog and biochemistry following changes in afferent activity and integrity. I will conduct detailed analyses in the chicken nucleus magnocellularis (NM) and nucleus laminaris (NL), a well-characterized animal model for studying auditory temporal processing and a tractable system for gene manipulation, and will extend some analyses to human brains. I will characterize the developmental profile of FMRP in chicken NM and NL using Western blot and immunocytochemistry, and identify the temporal correlations of FMRP with well-documented characteristics of dendritic development and specialized physiological properties. I will determine how knockdown of FMRP expression affects the development of dendritic morphology and expression of key proteins of chicken NM and NL neurons. Gene manipulations with temporal and spatial control, individual cell filling, immunocytochemistry, and high-resolution confocal microscopy will be used. I will determine how FMRP regulates afferent-dependent dendritic reorganization in chicken NL. I will first examine how afferent regulates FMRP and then assess the effects of FMRP knockdown on afferent influence of dendritic structure and biochemistry. Combined genetic and afferent manipulations, as well as confocal and multi-photon imaging of fixed and live tissues, will be used. In collaboration with Dr. Kulesza, we will start to explore potential function of FMRP in human auditory brainstem neurons by examining the temporal and spatial distribution of FMRP and FMRP-binding proteins in fixed human brainstem sections using immunocytochemistry. Overall, these studies will provide insight into FMRP regulation of dendritic arborization and specialized properties for auditory processing neurons, and insight into mechanisms of vertebrate neuronal development and disease pathology.

Public Health Relevance

Fragile X syndrome, the leading heritable cause of autism spectrum disorders, is caused by loss of the fragile X mental retardation protein (FMRP). This results in profound intellectual deficits and sensory dysfunction. It is imperative that we understand how FMRP regulates brain development and function to be able to therapeutically intervene in cases of fragile X syndrome and other types of autism. The prevalence of autism spectrum disorders has increased up to 1:88 in U.S. children and 1:2500 for fragile X syndrome, significantly affecting qualify of life of these patients and their family.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC013074-05
Application #
9402068
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Florida State University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
790877419
City
Tallahassee
State
FL
Country
United States
Zip Code
32306
Wang, Xiaoyu; Hong, Hui; Brown, David H et al. (2017) Distinct Neural Properties in the Low-Frequency Region of the Chicken Cochlear Nucleus Magnocellularis. eNeuro 4:
Wang, Yuan; Zorio, Diego A R; Karten, Harvey J (2017) Heterogeneous organization and connectivity of the chicken auditory thalamus (Gallus gallus). J Comp Neurol 525:3044-3071
Hong, Hui; Lu, Ting; Wang, Xiaoyu et al. (2017) Resurgent sodium current promotes action potential firing in the avian auditory brainstem. J Physiol :
Zorio, Diego A R; Jackson, Christine M; Liu, Yong et al. (2017) Cellular distribution of the fragile X mental retardation protein in the mouse brain. J Comp Neurol 525:818-849
Sakano, Hitomi; Zorio, Diego A R; Wang, Xiaoyu et al. (2017) Proteomic analyses of nucleus laminaris identified candidate targets of the fragile X mental retardation protein. J Comp Neurol 525:3341-3359
Weatherstone, Jessica H; Kopp-Scheinpflug, Conny; Pilati, Nadia et al. (2017) Maintenance of neuronal size gradient in MNTB requires sound-evoked activity. J Neurophysiol 117:756-766
Wang, Yuan; Sakano, Hitomi; Beebe, Karisa et al. (2014) Intense and specialized dendritic localization of the fragile X mental retardation protein in binaural brainstem neurons: a comparative study in the alligator, chicken, gerbil, and human. J Comp Neurol 522:2107-28
Beebe, K; Wang, Y; Kulesza, R (2014) Distribution of fragile X mental retardation protein in the human auditory brainstem. Neuroscience 273:79-91