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.

journal_name

J Neurochem

authors

Wang X,Snape M,Klann E,Stone JG,Singh A,Petersen RB,Castellani RJ,Casadesus G,Smith MA,Zhu X

doi

10.1111/j.1471-4159.2012.07722.x

subject

Has Abstract

pub_date

2012-05-01 00:00:00

pages

672-9

issue

4

eissn

0022-3042

issn

1471-4159

journal_volume

121

pub_type

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