title: Metabotropic glutamate receptor-mediated use-dependent down-regulation of synaptic excitability involves the fragile X mental retardation protein.
abstract: Loss of the mRNA-binding protein FMRP results in the most common inherited form of both mental retardation and autism spectrum disorders: fragile X syndrome (FXS). The leading FXS hypothesis proposes that metabotropic glutamate receptor (mGluR) signaling at the synapse controls FMRP function in the regulation of local protein translation to modulate synaptic transmission strength. In this study, we use the Drosophila FXS disease model to test the relationship between Drosophila FMRP (dFMRP) and the sole Drosophila mGluR (dmGluRA) in regulation of synaptic function, using two-electrode voltage-clamp recording at the glutamatergic neuromuscular junction (NMJ). Null dmGluRA mutants show minimal changes in basal synapse properties but pronounced defects during sustained high-frequency stimulation (HFS). The double null dfmr1;dmGluRA mutant shows repression of enhanced augmentation and delayed onset of premature long-term facilitation (LTF) and strongly reduces grossly elevated post-tetanic potentiation (PTP) phenotypes present in dmGluRA-null animals. Null dfmr1 mutants show features of synaptic hyperexcitability, including multiple transmission events in response to a single stimulus and cyclic modulation of transmission amplitude during prolonged HFS. The double null dfmr1;dmGluRA mutant shows amelioration of these defects but does not fully restore wildtype properties in dfmr1-null animals. These data suggest that dmGluRA functions in a negative feedback loop in which excess glutamate released during high-frequency transmission binds the glutamate receptor to dampen synaptic excitability, and dFMRP functions to suppress the translation of proteins regulating this synaptic excitability. Removal of the translational regulator partially compensates for loss of the receptor and, similarly, loss of the receptor weakly compensates for loss of the translational regulator.
authors.affiliation: Department of Biological Sciences, Vanderbilt University, VU Station B, Box 351634, Nashville, TN 37235-1634, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Repicky
authors.forename: Kendal
authors.initials: K
authors.lastname: Broadie
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D055592:Biophysical Phenomena; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology*; D004330:Drosophila; D004558:Electric Stimulation / Q000379:methods; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*
chemical_list: D002118:Calcium; D051860:Fragile X Messenger Ribonucleoprotein 1; D018094:Receptors, Metabotropic Glutamate