Abstract
Fragile X syndrome (FXS), a common form of inherited mental retardation, is caused by the lack of fragile X mental retardation protein (FMRP). The animal model of FXS, Fmr1 knockout mice, have deficits in the Morris water maze and trace fear memory tests, showing impairment in hippocampus-dependent learning and memory. However, results for synaptic long-term potentiation (LTP), a key cellular model for learning and memory, remain inconclusive in the hippocampus of Fmr1 knockout mice. Here, we demonstrate that FMRP is required for glycine induced LTP (Gly-LTP) in the CA1 of hippocampus. This form of LTP requires activation of post-synaptic NMDA receptors and metabotropic glutamateric receptors, as well as the subsequent activation of extracellular signal-regulated kinase (ERK) 1/2. However, paired-pulse facilitation was not affected by glycine treatment. Genetic deletion of FMRP interrupted the phosphorylation of ERK1/2, suggesting the possible role of FMRP in the regulation of the activity of ERK1/2. Our study provide strong evidences that FMRP participates in Gly-LTP in the hippocampus by regulating the phosphorylation of ERK1/2, and that improper regulation of these signaling pathways may contribute to the learning and memory deficits observed in FXS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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2-Amino-5-phosphonovalerate / pharmacology
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Alanine / analogs & derivatives
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Alanine / pharmacology
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Analysis of Variance
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Animals
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Biophysics
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Bromodeoxyuridine / metabolism
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Butadienes / pharmacology
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Electric Stimulation
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Fragile X Mental Retardation Protein / genetics
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Fragile X Mental Retardation Protein / physiology*
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GABA Antagonists / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Glycine / pharmacology
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Glycine Agents / pharmacology
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Hippocampus / cytology
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Hippocampus / drug effects
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Hippocampus / physiology*
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In Vitro Techniques
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Long-Term Potentiation / drug effects
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Long-Term Potentiation / genetics
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Long-Term Potentiation / physiology*
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Male
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Nitriles / pharmacology
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Patch-Clamp Techniques / methods
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Picrotoxin / pharmacology
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Pyramidal Cells / drug effects
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Pyramidal Cells / physiology
Substances
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Butadienes
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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Fmr1 protein, mouse
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GABA Antagonists
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Glycine Agents
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Nitriles
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U 0126
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2-amino-3-phosphonopropionic acid
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Picrotoxin
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Fragile X Mental Retardation Protein
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2-Amino-5-phosphonovalerate
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Mitogen-Activated Protein Kinase Kinases
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Bromodeoxyuridine
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Alanine
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Glycine