This proposal is designed to investigate the biochemical signaling mechanisms underlying metabotropic glutamate receptor-dependent (mGluR) long-term depression (LTD) and late-phase long-term potentiation (L-LTP) in area CA1 of the mouse hippocampus. These forms of synaptic plasticity previously have been shown to be dependent on new protein synthesis. However, virtually nothing is known about the signaling cascades that couple either mGluRs or N-methyl-D-aspartate (NMDA) receptors to the protein translation machinery during these forms of plasticity. If both mGluR-LTD and L-LTP are both dependent on protein synthesis, then several critical questions arise. Are the same signaling pathways required to couple mGluRs and NMDA receptors to the translation machinery during mGluR-LTD and L-LTP, respectively? Are there mRNAs that are preferentially translated during mGluR-LTD versus L-LTP? Using a combination of biochemical, immunocytochemical, pharmacological, and electrophysiological techniques, as well as genetically-modified mice, we propose to 1) test the hypothesis that cap-dependent translation signaling pathways are involved in mGluR-dependent LTD and late-phase LTP, 2) test the hypothesis that S6-directed translation signaling pathways are involved in mGluR-dependent LTD and late-phase LTP, and 3) test the hypothesis that fragile X mental retardation protein is involved in the regulation of mGluR-dependent LTD but not late-phase LTP, and that translation is regulated improperly during mGluR-dependent LTD in mouse models of fragile X mental retardation. These studies should provide insights into the signaling cascades that couple mGluRs and NMDA receptors to protein translation forms of synaptic plasticity that may be important for learning and memory. These studies may also elucidate unique signaling cascades in the hippocampus that will be critical for understanding the behavioral abnormalities and memory impairments associated with fragile X mental retardation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047384-02
Application #
7033830
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Talley, Edmund M
Project Start
2005-07-01
Project End
2006-08-31
Budget Start
2006-07-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$79,062
Indirect Cost
Name
Baylor College of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Santini, Emanuela; Huynh, Thu N; Longo, Francesco et al. (2017) Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice. Sci Signal 10:
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Bowling, Heather; Bhattacharya, Aditi; Klann, Eric et al. (2016) Deconstructing brain-derived neurotrophic factor actions in adult brain circuits to bridge an existing informational gap in neuro-cell biology. Neural Regen Res 11:363-7
Bhattacharya, Aditi; Mamcarz, Maggie; Mullins, Caitlin et al. (2016) Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice. Neuropsychopharmacology 41:1991-2000
Bowling, Heather; Bhattacharya, Aditi; Zhang, Guoan et al. (2016) BONLAC: A combinatorial proteomic technique to measure stimulus-induced translational profiles in brain slices. Neuropharmacology 100:76-89
Sethna, Ferzin; Zhang, Ming; Kaphzan, Hanoch et al. (2016) Calmodulin activity regulates group I metabotropic glutamate receptor-mediated signal transduction and synaptic depression. J Neurosci Res 94:401-8
Richter, Joel D; Bassell, Gary J; Klann, Eric (2015) Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat Rev Neurosci 16:595-605
Huynh, Thu N; Shah, Manan; Koo, So Yeon et al. (2015) eIF4E/Fmr1 double mutant mice display cognitive impairment in addition to ASD-like behaviors. Neurobiol Dis 83:67-74

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