Fragile X Syndrome (FXS) is the most common inherited form of mental retardation and is caused by loss of function mutations in the Fragile X Mental Retardation gene (FMR1). Patients with FXS as well as other forms of mental retardation have an excess of dendritic spines as well as longer spines, suggesting that abnormal postsynaptic function, development or plasticity contributes to the cognitive deficits of this disease. Fragile X Mental Retardation Protein (FMRP), the protein product of FMR1, is an RNA binding protein and is thought to regulate translation of proteins in dendrites and dendritic spines. Such local or synaptic protein synthesis regulates both synapse development and long-term plasticity in mature animals. Therefore, FMRP most likely mediates its neuronal effects through translational regulation of synaptic proteins. Consistent with this idea, we and others have discovered that FMRP regulates synapse pruning in adolescent neurons as well as long-term synaptic depression by metabotropic glutamate receptors (mGluRs). Exactly how FMRP regulates synapse development and plasticity is unknown. Whether these effects are due to translational regulation of dendritically synthesized proteins or the identity of such proteins is also unknown. Here we propose to examine the cellular mechanisms by which FMRP regulates synapse development and mGluR- dependent synaptic plasticity. We will also examine how FMRP regulates the synthesis of proteins in dendrites and test 2 candidate proteins for their role in FMRP mediated synaptic pruning and mGluR-induced synaptic depression. Developing and testing new therapeutic strategies for treatment of FXS and autism, such as mGluR antagonists, is a mission of the NIH. Our results are expected to provide knowledge of how FMRP, or its absence, regulates synapse maturation and mGluR-dependent synaptic plasticity in the adult. These results will help to determine the neurobiological basis of mental retardation and related disorders such as autism as well as test if mGluR antagonists are a suitable therapeutic strategy for FXS.
The specific aims of the grant are: 1. Examine FMRP regulation of synapse development and elimination. 2 Determine the role of FMRP phosphorylation in regulation of synapse number and mGluR-induced dendritic protein synthesis, 3. Determine if FMRP is an acute regulator of LTD, 4. Test candidate proteins for their involvement in LTD and FMRP induced synapse elimination.Fragile X Syndrome (FXS) is the most common inherited form of mental retardation and a leading cause of autism. FXS is caused by loss of function mutations in the Fragile X Mental Retardation protein (FMRP). Our research will determine how FMRP normally works in the brain as well as how and why the brain functions differently without FMRP. This work is expected to provide important knowledge to development therapies for mental retardation and autism.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD052731-05
Application #
8223292
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Urv, Tiina K
Project Start
2008-02-08
Project End
2013-09-24
Budget Start
2012-02-01
Budget End
2013-09-24
Support Year
5
Fiscal Year
2012
Total Cost
$317,077
Indirect Cost
$115,117
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Wilkerson, Julia R; Albanesi, Joseph P; Huber, Kimberly M (2018) Roles for Arc in metabotropic glutamate receptor-dependent LTD and synapse elimination: Implications in health and disease. Semin Cell Dev Biol 77:51-62
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Chang, Chia-Wei; Wilkerson, Julia R; Hale, Carly F et al. (2017) Distinct stages of synapse elimination are induced by burst firing of CA1 neurons and differentially require MEF2A/D. Elife 6:
Tsai, Nien-Pei; Huber, Kimberly M (2017) Protocadherins and the Social Brain. Biol Psychiatry 81:173-174
Tsai, Nien-Pei; Wilkerson, Julia R; Guo, Weirui et al. (2017) FMRP-dependent Mdm2 dephosphorylation is required for MEF2-induced synapse elimination. Hum Mol Genet 26:293-304
Harrington, Adam J; Raissi, Aram; Rajkovich, Kacey et al. (2016) MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders. Elife 5:
Zhang, Zilai; Cao, Mou; Chang, Chia-Wei et al. (2016) Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling. Mol Cell Biol 36:70-83
Loerwald, Kristofer W; Patel, Ankur B; Huber, Kimberly M et al. (2015) Postsynaptic mGluR5 promotes evoked AMPAR-mediated synaptic transmission onto neocortical layer 2/3 pyramidal neurons during development. J Neurophysiol 113:786-95
Byers, Christopher E; Barylko, Barbara; Ross, Justin A et al. (2015) Enhancement of dynamin polymerization and GTPase activity by Arc/Arg3.1. Biochim Biophys Acta 1850:1310-8
Wilkerson, Julia R; Tsai, Nien-Pei; Maksimova, Marina A et al. (2014) A role for dendritic mGluR5-mediated local translation of Arc/Arg3.1 in MEF2-dependent synapse elimination. Cell Rep 7:1589-1600

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