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The Journal of Neuroscience, August 31, 2005, 25(35):8048-8055; doi:10.1523/JNEUROSCI.1777-05.2005
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Neurobiology of Disease
Prolonged Epileptiform Discharges Induced by Altered Group I Metabotropic Glutamate Receptor-Mediated Synaptic Responses in Hippocampal Slices of a Fragile X Mouse Model
Shih-Chieh Chuang,1 Wangfa Zhao,1 Robert Bauchwitz,2 Qijiang Yan,2 Riccardo Bianchi,1 andRobert K. S. Wong1 1Department of Physiology and Pharmacology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York 11203, and 2Department of Neurology, St. Luke's Roosevelt Institute for Health Sciences, Columbia University, New York, New York 10019
Mutations in FMR1, which encodes the fragile X mental retardation protein (FMRP), are the cause of fragile X syndrome (FXS), an X-linked mental retardation disorder. Inactivation of the mouse gene Fmr1 confers a number of FXS-like phenotypes including an enhanced susceptibility to epileptogenesis during development. We find that in a FXS mouse model, in which the function of FMRP is suppressed, synaptically released glutamate induced prolonged epileptiform discharges resulting from enhanced group I metabotropic glutamate receptor (mGluR)-mediated responses in hippocampal slices. The induction of the group I mGluR-mediated, prolonged epileptiform discharges was inhibited in preparations that were pretreated with inhibitors of ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation or of mRNA translation, and their maintenance was suppressed by group I mGluR antagonists. The results suggest that FMRP plays a key role in the control of signaling at the recurrent glutamatergic synapses in the hippocampus. The absence of this control causes the synaptically activated group I mGluRs to elicit translation-dependent epileptogenic activities.
Key words: mGluR; epilepsy; FMRP; fragile X; synaptic plasticity; synchronization
Received May 3, 2005; revised July 7, 2005; accepted July 28, 2005.
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