title: Altered cerebral protein synthesis in fragile X syndrome: studies in human subjects and knockout mice.
abstract: Dysregulated protein synthesis is thought to be a core phenotype of fragile X syndrome (FXS). In a mouse model (Fmr1 knockout (KO)) of FXS, rates of cerebral protein synthesis (rCPS) are increased in selective brain regions. We hypothesized that rCPS are also increased in FXS subjects. We measured rCPS with the L-[1-(11)C]leucine positron emission tomography (PET) method in whole brain and 10 regions in 15 FXS subjects who, because of their impairments, were studied under deep sedation with propofol. We compared results with those of 12 age-matched controls studied both awake and sedated. In controls, we found no differences in rCPS between awake and propofol sedation. Contrary to our hypothesis, FXS subjects under propofol sedation had reduced rCPS in whole brain, cerebellum, and cortex compared with sedated controls. To investigate whether propofol could have a disparate effect in FXS subjects masking usually elevated rCPS, we measured rCPS in C57Bl/6 wild-type (WT) and KO mice awake or under propofol sedation. Propofol decreased rCPS substantially in most regions examined in KO mice, but in WT mice caused few discrete changes. Propofol acts by decreasing neuronal activity either directly or by increasing inhibitory synaptic activity. Our results suggest that changes in synaptic signaling can correct increased rCPS in FXS.
authors.affiliation: Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Qin
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Schmidt
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Zametkin
authors.forename: Shrinivas
authors.initials: S
authors.lastname: Bishu
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Horowitz
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Burlin
authors.forename: Zengyan
authors.initials: Z
authors.lastname: Xia
authors.forename: Tianjiang
authors.initials: T
authors.lastname: Huang
authors.forename: Zenaide M
authors.initials: ZM
authors.lastname: Quezado
authors.forename: Carolyn Beebe
authors.initials: CB
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography; D015742:Propofol / Q000008:administration & dosage; D014176:Protein Biosynthesis; D011859:Radiography; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D006993:Hypnotics and Sedatives; D015742:Propofol; C497684:Fmr1 protein, mouse