Prolonged Epileptiform Discharges Induced by Altered Group I Metabotropic Glutamate Receptor-Mediated Synaptic Responses in Hippocampal Slices of a Fragile X Mouse Model

Abstract

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.

Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome

“…Next, we examined if this LTP deficit could be caused by abnormal action potential firing in LA neurons, because mGluRs are known to underlie pathological firing patterns in the hippocampus of Fmr1 KO mice (22). We detected no difference in EPSP-Spike (E-S) coupling, an index of the probability of firing an action potential for a given synaptic strength (Fig.…”

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…In Fmr1 KO mice, dysregulated neuronal connectivity in the barrel cortex (Bureau et al, 2008) leads to defective glutamatergic synapse maturation, delayed and aberrant formation of sensory maps, and altered synaptic plasticity during the critical period (Harlow et al, 2010). In general, loss of FMRP seems to lead to altered network synchrony and hyperexcitable neuronal networks (Chuang et al, 2005;Gibson et al, 2008).…”

“…Subsequent work also suggested that apart from hippocampal LTD, additional mGlu 1/5 -dependent neuronal mechanisms are dysregulated in the FXS brain. In the hippocampus, deletion of FMRP was shown to lead to prolonged epileptiform discharges caused by enhanced sensitivity of mGlu 1/5 to synaptically released glutamate (Chuang et al, 2005). Loss of FMRP also leads to changes in mGlu 1/5 -mediated endocannabinoid (eCB) synthesis and release in the hippocampus (Zhang and Alger, 2010).…”

Fragile X: Translation in Action

“…In the case of mGluR5-dependent protein synthesis, one of these negative regulators might be FMRP. In the absence of FMRP, one might expect that the protein synthesis-dependent consequences of mGluR5 activation would be exaggerated-and indeed this is the case (Huber et al, 2002;Chuang et al, 2005).…”