title: Activation of the extracellular signal-regulated kinase pathway contributes to the behavioral deficit of fragile x-syndrome.
abstract: Fragile X syndrome (FXS) is a developmental disorder caused by the loss of Fragile X Mental Retardation 1 (FMR1) gene function because of a CGG repeat expansion (> 200 repeats) in the gene. The molecular mechanism(s) linking loss of FMR1 function to the molecular pathology and cognitive/behavioral disability remain unclear. Given the critical role of extracellular signal-regulated kinase (ERK) in synaptic plasticity and neurodevelopment, a number of recent studies have investigated ERK phosphorylation under basal conditions or upon mGluR-induction using neuronal and peripheral tissues from Fmr1 knockout mice and peripheral tissues from FXS patients. However, these reports have presented conflicting results. The current study is the first to focus on the levels of ERK phosphorylation in brain tissue from human FXS patients. In both human brain tissue and brain tissue from Fmr1 knockout mice there was significantly increased phosphorylation of MEK1/2 and ERK. Indeed, treating Fmr1 knockout mice with the MEK1/2 inhibitor SL327 abrogated audiogenic seizure activity, a feature of the Fmr1 knockout mice that replicates the symptom in patients with FXS. These findings suggest that activation of the ERK pathway results in some cardinal cognitive and clinical features in FXS patients and likely have profound translational implications.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Xinglong
authors.initials: X
authors.lastname: Wang
authors.forename: Mike
authors.initials: M
authors.lastname: Snape
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Stone
authors.forename: Avneet
authors.initials: A
authors.lastname: Singh
authors.forename: Robert B
authors.initials: RB
authors.lastname: Petersen
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Castellani
authors.forename: Gemma
authors.initials: G
authors.lastname: Casadesus
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002648:Child; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics / Q000523:psychology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D012640:Seizures / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D055815:Young Adult
chemical_list: D000607:Aminoacetonitrile; D048049:Extracellular Signal-Regulated MAP Kinases; D051860:Fragile X Messenger Ribonucleoprotein 1; D011480:Protease Inhibitors; C497684:Fmr1 protein, mouse; C424127:SL 327