title: Decreased fragile X mental retardation protein expression underlies amygdala dysfunction in carriers of the fragile X premutation.
abstract: BACKGROUND
  The fragile X premutation provides a unique opportunity for the study of genetic and brain mechanisms of behavior and cognition in the context of neurodevelopment and neurodegeneration. Although the neurodegenerative phenotype, fragile X-associated tremor/ataxia syndrome, is well described, evidence of a causal link between the premutation and psychiatric disorder earlier in life, clear delineation of a behavioral/cognitive phenotype, and characterization of the physiological basis of observed symptoms have been elusive.
  
  
  METHODS
  We completed functional magnetic resonance imaging targeting the amygdala with an emotion-matching task and concurrent infrared eye tracking, FMR1 molecular genetic testing, and neuropsychological assessment in 23 men with the premutation (mean age = 32.9 years) and 25 male control subjects (mean age = 30.1 years).
  
  
  RESULTS
  Premutation carriers had significantly smaller left and right amygdala volume and reduced right amygdala activation during the task relative to control subjects. Although both elevated FMR1 messenger RNA and reduced fragile X mental retardation protein (FMRP) were associated with the reduced activation, multiple regression analysis suggested that reduced FMRP is the primary factor. Premutation carriers also had higher ratings of autism spectrum symptoms than control subjects, which were associated with the reduced amygdala response.
  
  
  CONCLUSIONS
  Although prior studies have emphasized a toxic gain-of-function effect of elevated messenger RNA associated with the premutation, the current results point to the role of reduced FMRP in alterations of brain activity and behavior.
authors.affiliation: Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California-Davis, Medical Center, Sacramento, California 95817, USA. david.hessl@ucdmc.ucdavis.edu
authors.forename: David
authors.initials: D
authors.lastname: Hessl
authors.forename: John M
authors.initials: JM
authors.lastname: Wang
authors.forename: Andrea
authors.initials: A
authors.lastname: Schneider
authors.forename: Kami
authors.initials: K
authors.lastname: Koldewyn
authors.forename: Lien
authors.initials: L
authors.lastname: Le
authors.forename: Christine
authors.initials: C
authors.lastname: Iwahashi
authors.forename: Katherine
authors.initials: K
authors.lastname: Cheung
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hagerman
authors.forename: Susan M
authors.initials: SM
authors.lastname: Rivera
mesh_terms: D000328:Adult; D000679:Amygdala / Q000473:pathology*; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D001921:Brain / Q000473:pathology; D003071:Cognition / Q000502:physiology; D004247:DNA / Q000235:genetics; D004644:Emotions / Q000502:physiology; D005133:Eye Movements / Q000502:physiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000096:biosynthesis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007361:Intelligence Tests; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D011597:Psychomotor Performance / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004247:DNA; D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger