Extracellular glutamate exposure facilitates group I mGluR-mediated epileptogenesis in the hippocampus

• Published in: The Journal of neuroscience Vol. 35; no. 1; pp. 308 - 315
• Main Authors: Zhao, Wangfa, Chuang, Shih-Chieh, Young, Steven R, Bianchi, Riccardo, Wong, Robert K S
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 07.01.2015
• Subjects: Animals; Epilepsy - chemically induced; Epilepsy - genetics; Epilepsy - metabolism; Extracellular Space - drug effects; Extracellular Space - metabolism; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Glutamic Acid - toxicity; Hippocampus - drug effects; Hippocampus - metabolism; Mice; Mice, 129 Strain; Mice, Knockout; Organ Culture Techniques; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - physiology; epilepsy; plasticity; protein synthesis; seizure; metabotropic glutamate receptor; proteolysis
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1944-14.2015

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.