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; 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 7:1589-600
Patel, Ankur B; Loerwald, Kristofer W; Huber, Kimberly M et al. (2014) Postsynaptic FMRP promotes the pruning of cell-to-cell connections among pyramidal neurons in the L5A neocortical network. J Neurosci 34:3413-8
Patel, Ankur B; Hays, Seth A; Bureau, Ingrid et al. (2013) A target cell-specific role for presynaptic Fmr1 in regulating glutamate release onto neocortical fast-spiking inhibitory neurons. J Neurosci 33:2593-604
Jakkamsetti, Vikram; Tsai, Nien-Pei; Gross, Christina et al. (2013) Experience-induced Arc/Arg3.1 primes CA1 pyramidal neurons for metabotropic glutamate receptor-dependent long-term synaptic depression. Neuron 80:72-9
Zang, Tong; Maksimova, Marina A; Cowan, Christopher W et al. (2013) Postsynaptic FMRP bidirectionally regulates excitatory synapses as a function of developmental age and MEF2 activity. Mol Cell Neurosci 56:39-49
Niere, Farr; Wilkerson, Julia R; Huber, Kimberly M (2012) Evidence for a fragile X mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered Arc translation and long-term depression. J Neurosci 32:5924-36
Ronesi, Jennifer A; Collins, Katie A; Hays, Seth A et al. (2012) Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat Neurosci 15:431-40, S1
Hays, Seth A; Huber, Kimberly M; Gibson, Jay R (2011) Altered neocortical rhythmic activity states in Fmr1 KO mice are due to enhanced mGluR5 signaling and involve changes in excitatory circuitry. J Neurosci 31:14223-34
Pfeiffer, Brad E; Zang, Tong; Wilkerson, Julia R et al. (2010) Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron 66:191-7
Luscher, Christian; Huber, Kimberly M (2010) Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65:445-59

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