Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a fragile X mouse model.
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.
Chuang
Shih-Chieh
SC
Department of Physiology and Pharmacology, State University of New York Health Science Center, Brooklyn, New York 11203, USA.
Zhao
Wangfa
W
Bauchwitz
Robert
R
Yan
Qijiang
Q
Bianchi
Riccardo
R
Wong
Robert K S
RK
D000818:Animals; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1