title: Extracellular glutamate exposure facilitates group I mGluR-mediated epileptogenesis in the hippocampus.
abstract: Stimulation of group I mGluRs elicits several forms of translation-dependent neuronal plasticity including epileptogenesis. The translation process underlying plasticity induction is controlled by repressors including the fragile X mental retardation protein (FMRP). In the absence of FMRP-mediated repression, a condition that occurs in a mouse model (Fmr1(-/-)) of fragile X syndrome, group I mGluR-activated translation is exaggerated causing enhanced seizure propensity. We now show that glutamate exposure (10 μm for 30 min) reduced FMRP levels in wild-type mouse hippocampal slices. Downregulation of FMRP was dependent on group I mGluR activation and was blocked by a proteasome inhibitor (MG-132). Following glutamate exposure, synaptic stimulation induced prolonged epileptiform discharges with properties similar to those observed in Fmr1(-/-) preparations. In both cases, prolonged epileptiform discharges were blocked by group I mGluR antagonists (LY367385 + MPEP) and their induction was prevented by protein synthesis inhibitor (anisomycin). The results suggest that stimulation of group I mGluRs during glutamate exposure caused proteolysis of FMRP. Reduction of FMRP led to enhanced synaptic group I mGluR-mediated translation. Elevated translation facilitated the recruitment of group I mGluR-mediated prolonged epileptiform discharges.
authors.affiliation: The Robert F. Furchgott Center for Neural and Behavioral Science, and Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York 11203.
authors.forename: Wangfa
authors.initials: W
authors.lastname: Zhao
authors.affiliation: The Robert F. Furchgott Center for Neural and Behavioral Science, and Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York 11203.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Chuang
authors.affiliation: The Robert F. Furchgott Center for Neural and Behavioral Science, and Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York 11203.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Young
authors.affiliation: The Robert F. Furchgott Center for Neural and Behavioral Science, and Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York 11203.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bianchi
authors.affiliation: The Robert F. Furchgott Center for Neural and Behavioral Science, and Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York 11203 bwong@downstate.edu.
authors.forename: Robert K S
authors.initials: RK
authors.lastname: Wong
mesh_terms: D000818:Animals; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D018698:Glutamic Acid; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C104077:metabotropic glutamate receptor type 1
keywords: epilepsy; metabotropic glutamate receptor; plasticity; protein synthesis; proteolysis; seizure