title: Impaired activity-dependent FMRP translation and enhanced mGluR-dependent LTD in Fragile X premutation mice.
abstract: Fragile X premutation-associated disorders, including Fragile X-associated Tremor Ataxia Syndrome, result from unmethylated CGG repeat expansions in the 5' untranslated region (UTR) of the FMR1 gene. Premutation-sized repeats increase FMR1 transcription but impair rapid translation of the Fragile X mental retardation protein (FMRP), which is absent in Fragile X Syndrome (FXS). Normally, FMRP binds to RNA and regulates metabotropic glutamate receptor (mGluR)-mediated synaptic translation, allowing for dendritic synthesis of several proteins. FMRP itself is also synthesized at synapses in response to mGluR activation. However, the role of activity-dependent translation of FMRP in synaptic plasticity and Fragile X-premutation-associated disorders is unknown. To investigate this question, we utilized a CGG knock-in mouse model of the Fragile X premutation with 120-150 CGG repeats in the mouse Fmr1 5' UTR. These mice exhibit increased Fmr1 mRNA production but impaired FMRP translational efficiency, leading to a modest reduction in basal FMRP expression. Cultured hippocampal neurons and synaptoneurosomes derived from CGG KI mice demonstrate impaired FMRP translation in response to the group I mGluR agonist 3,5-dihydroxyphenylglycine. Electrophysiological analysis reveals enhanced mGluR-mediated long-term depression (mGluR-LTD) at CA3-CA1 synapses in acute hippocampal slices prepared from CGG KI mice relative to wild-type littermates, similar to Fmr1 knockout mice. However, unlike mGluR-LTD in mice completely lacking FMRP, mGluR-LTD in CGG knock-in mice remains dependent on new protein synthesis. These studies demonstrate partially overlapping synaptic plasticity phenotypes in mouse models of FXS and Fragile X premutation disorders and support a role for activity-dependent synthesis of FMRP in enduring forms of synaptic plasticity.
authors.affiliation: Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Iliff
authors.forename: Abigail J
authors.initials: AJ
authors.lastname: Renoux
authors.forename: Amy
authors.initials: A
authors.lastname: Krans
authors.forename: Karen
authors.initials: K
authors.lastname: Usdin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sutton
authors.forename: Peter K
authors.initials: PK
authors.lastname: Todd
mesh_terms: D000818:Animals; D003712:Dendrites / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D055879:Gene Knock-In Techniques; D006801:Humans; D036881:Long-Term Synaptic Depression; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D014176:Protein Biosynthesis; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse