title: Fragile X mental retardation protein regulates heterosynaptic plasticity in the hippocampus.
abstract: Silencing of a single gene, FMR1, is linked to a highly prevalent form of mental retardation, characterized by social and cognitive impairments, known as fragile X syndrome (FXS). The FMR1 gene encodes fragile X mental retardation protein (FMRP), which negatively regulates translation. Knockout of Fmr1 in mice results in enhanced long-term depression (LTD) induced by metabotropic glutamate receptor (mGluR) activation. Despite the evidence implicating FMRP in LTD, the role of FMRP in long-term potentiation (LTP) is less clear. Synaptic strength can be augmented heterosynaptically through the generation and sequestration of plasticity-related proteins, in a cell-wide manner. If heterosynaptic plasticity is altered in Fmr1 knockout (KO) mice, this may explain the cognitive deficits associated with FXS. We induced homosynaptic plasticity using the β-adrenergic receptor (β-AR) agonist, isoproterenol (ISO), which facilitated heterosynaptic LTP that was enhanced in Fmr1 KO mice relative to wild-type (WT) controls. To determine if enhanced heterosynaptic LTP in Fmr1 KO mouse hippocampus requires protein synthesis, we applied a translation inhibitor, emetine (EME). EME blocked homo- and heterosynaptic LTP in both genotypes. We also probed the roles of mTOR and ERK in boosting heterosynaptic LTP in Fmr1 KO mice. Although heterosynaptic LTP was blocked in both WT and KOs by inhibitors of mTOR and ERK, homosynaptic LTP was still enhanced following mTOR inhibition in slices from Fmr1 KO mice. Because mTOR will normally stimulate translation initiation, our results suggest that β-AR stimulation paired with derepression of translation results in enhanced heterosynaptic plasticity.
authors.affiliation: Centre for Neuroscience, University of Alberta School of Medicine, Edmonton, AB T6G2H7, Canada.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Connor
authors.forename: Charles A
authors.initials: CA
authors.lastname: Hoeffer
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
authors.forename: Peter V
authors.initials: PV
authors.lastname: Nguyen
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001703:Biophysics; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D004640:Emetine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics*; D005419:Flavonoids / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors; D020668:rap GTP-Binding Proteins / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D001640:Bicuculline; D004640:Emetine; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005419:Flavonoids; D051860:Fragile X Messenger Ribonucleoprotein 1; D058787:GABA-A Receptor Antagonists; D007166:Immunosuppressive Agents; D007545:Isoproterenol; D011725:Pyridines; D020123:Sirolimus; D020668:rap GTP-Binding Proteins; C497684:Fmr1 protein, mouse; C121465:6-methyl-2-(phenylethynyl)pyridine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one