u-0126 and 2-amino-3-phosphonopropionic-acid

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.

Topics: 2-Amino-5-phosphonovalerate; Alanine; Analysis of Variance; Animals; Biophysics; Bromodeoxyuridine; Butadienes; Electric Stimulation; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Fragile X Mental Retardation Protein; GABA Antagonists; Gene Expression Regulation; Glycine; Glycine Agents; Hippocampus; In Vitro Techniques; Long-Term Potentiation; Male; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase Kinases; Nitriles; Patch-Clamp Techniques; Picrotoxin; Pyramidal Cells