title: R-Baclofen Reverses a Social Behavior Deficit and Elevated Protein Synthesis in a Mouse Model of Fragile X Syndrome.
abstract: BACKGROUND
  Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability and the single genomic cause of autism spectrum disorders. It is caused by the absence of a fragile X mental retardation gene (Fmr1) product, FMRP, an RNA-binding translation suppressor. Elevated rates of protein synthesis in the brain and an imbalance between synaptic signaling via glutamate and γ-aminobutyric acid (GABA) are both considered important in the pathogenesis of FXS. In a mouse model of FXS (Fmr1 knockout [KO]), treatment with R-baclofen reversed some behavioral and biochemical phenotypes. A remaining crucial question is whether R-baclofen is also able to reverse increased brain protein synthesis rates.
  
  
  METHODS
  To answer this question, we measured regional rates of cerebral protein synthesis in vivo with the L-[1-(14)C]leucine method in vehicle- and R-baclofen-treated wildtype and Fmr1 KO mice. We further probed signaling pathways involved in the regulation of protein synthesis.
  
  
  RESULTS
  Acute R-baclofen administration corrected elevated protein synthesis and reduced deficits on a test of social behavior in adult Fmr1 KO mice. It also suppressed activity of the mammalian target of rapamycin pathway, particularly in synaptosome-enriched fractions, but it had no effect on extracellular-regulated kinase 1/2 activity. Ninety min after R-baclofen treatment, we observed an increase in metabotropic glutamate receptor 5 expression in the frontal cortex, a finding that may shed light on the tolerance observed in human studies with this drug.
  
  
  CONCLUSIONS
  Our results suggest that treatment via activation of the GABA (GABA receptor subtype B) system warrants further study in patients with FXS.
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Drs Qin, Huang, Kader, Krych, Xia, Burlin, Zeidler, Zhao, and Smith).
authors.forename: Mei
authors.initials: M
authors.lastname: Qin
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Drs Qin, Huang, Kader, Krych, Xia, Burlin, Zeidler, Zhao, and Smith).
authors.forename: Tianjian
authors.initials: T
authors.lastname: Huang
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Drs Qin, Huang, Kader, Krych, Xia, Burlin, Zeidler, Zhao, and Smith).
authors.forename: Michael
authors.initials: M
authors.lastname: Kader
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Drs Qin, Huang, Kader, Krych, Xia, Burlin, Zeidler, Zhao, and Smith).
authors.forename: Leland
authors.initials: L
authors.lastname: Krych
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Drs Qin, Huang, Kader, Krych, Xia, Burlin, Zeidler, Zhao, and Smith).
authors.forename: Zengyan
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Drs Qin, Huang, Kader, Krych, Xia, Burlin, Zeidler, Zhao, and Smith).
authors.forename: Thomas
authors.initials: T
authors.lastname: Burlin
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Drs Qin, Huang, Kader, Krych, Xia, Burlin, Zeidler, Zhao, and Smith).
authors.forename: Zachary
authors.initials: Z
authors.lastname: Zeidler
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Drs Qin, Huang, Kader, Krych, Xia, Burlin, Zeidler, Zhao, and Smith).
authors.forename: Tingrui
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Drs Qin, Huang, Kader, Krych, Xia, Burlin, Zeidler, Zhao, and Smith) beebe@mail.nih.gov.
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Smith
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000188:drug therapy*; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014176:Protein Biosynthesis / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D012919:Social Behavior; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D001418:Baclofen; D051860:Fragile X Messenger Ribonucleoprotein 1; D058786:GABA-B Receptor Agonists; D058570:TOR Serine-Threonine Kinases; C497684:Fmr1 protein, mouse; C546843:mTOR protein, mouse
keywords: Fragile X syndrome; R-baclofen; mTOR; protein synthesis; social behavior
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