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Reversal of disease-related pathologies in the fragile x mouse model by selective activation of gaba(b) receptors with arbaclofen

Academic Article
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Overview

authors

  • Henderson, C.
  • Wijetunge, L.
  • Kinoshita, M. N.
  • Shumway, M.
  • Hammond, R. S.
  • Postma, F. R.
  • Brynczka, C.
  • Rush, R.
  • Thomas, A.
  • Paylor, R.
  • Warren, S. T.
  • Vanderklish, Peter
  • Kind, P. C.
  • Carpenter, R. L.
  • Bear, M. F.
  • Healy, A. M.

publication date

  • September 2012

journal

  • Science Translational Medicine  Journal

abstract

  • Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism, results from the transcriptional silencing of FMR1 and loss of the mRNA translational repressor protein fragile X mental retardation protein (FMRP). Patients with FXS exhibit changes in neuronal dendritic spine morphology, a pathology associated with altered synaptic function. Studies in the mouse model of fragile X have shown that loss of FMRP causes excessive synaptic protein synthesis, which results in synaptic dysfunction and altered spine morphology. We tested whether the pharmacologic activation of the γ-aminobutyric acid type B (GABA(B)) receptor could correct or reverse these phenotypes in Fmr1-knockout mice. Basal protein synthesis, which is elevated in the hippocampus of Fmr1-knockout mice, was corrected by the in vitro application of the selective GABA(B) receptor agonist STX209 (arbaclofen, R-baclofen). STX209 also reduced to wild-type values the elevated AMPA receptor internalization in Fmr1-knockout cultured neurons, a known functional consequence of increased protein synthesis. Acute administration of STX209 in vivo, at doses that modify behavior, decreased mRNA translation in the cortex of Fmr1-knockout mice. Finally, the chronic administration of STX209 in juvenile mice corrected the increased spine density in Fmr1-knockout mice without affecting spine density in wild-type mice. Thus, activation of the GABA(B) receptor with STX209 corrected synaptic abnormalities considered central to fragile X pathophysiology, a finding that suggests that STX209 may be a potentially effective therapy to treat the core symptoms of FXS.

subject areas

  • Animals
  • Baclofen
  • Behavior, Animal
  • Dendritic Spines
  • Disease Models, Animal
  • Drinking Water
  • Fragile X Mental Retardation Protein
  • Fragile X Syndrome
  • GABA-B Receptor Agonists
  • Hippocampus
  • Male
  • Mice
  • Mice, Knockout
  • Phenotype
  • Polyribosomes
  • Protein Biosynthesis
  • Protein Transport
  • Receptors, AMPA
  • Receptors, GABA-B
  • Seizures
  • Synapses
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Identity

International Standard Serial Number (ISSN)

  • 1946-6234

Digital Object Identifier (DOI)

  • 10.1126/scitranslmed.3004218

PubMed ID

  • 22993295
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Additional Document Info

start page

  • 152ra128

volume

  • 4

issue

  • 152

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