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Int J Neuropsychopharmacol. 2015 Mar 28;18(9). pii: pyv034. doi: 10.1093/ijnp/pyv034.

R-Baclofen Reverses a Social Behavior Deficit and Elevated Protein Synthesis in a Mouse Model of Fragile X Syndrome.

Author information

1
Section on Neuroadaptation and Protein Metabolism, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Drs Qin, Huang, Kader, Krych, Xia, Burlin, Zeidler, Zhao, and Smith).
2
Section on Neuroadaptation and Protein Metabolism, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Drs Qin, Huang, Kader, Krych, Xia, Burlin, Zeidler, Zhao, and Smith) beebe@mail.nih.gov.

Abstract

BACKGROUND:

Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability and the single genomic cause of autism spectrum disorders. It is caused by the absence of a fragile X mental retardation gene (Fmr1) product, FMRP, an RNA-binding translation suppressor. Elevated rates of protein synthesis in the brain and an imbalance between synaptic signaling via glutamate and γ-aminobutyric acid (GABA) are both considered important in the pathogenesis of FXS. In a mouse model of FXS (Fmr1 knockout [KO]), treatment with R-baclofen reversed some behavioral and biochemical phenotypes. A remaining crucial question is whether R-baclofen is also able to reverse increased brain protein synthesis rates.

METHODS:

To answer this question, we measured regional rates of cerebral protein synthesis in vivo with the L-[1-(14)C]leucine method in vehicle- and R-baclofen-treated wildtype and Fmr1 KO mice. We further probed signaling pathways involved in the regulation of protein synthesis.

RESULTS:

Acute R-baclofen administration corrected elevated protein synthesis and reduced deficits on a test of social behavior in adult Fmr1 KO mice. It also suppressed activity of the mammalian target of rapamycin pathway, particularly in synaptosome-enriched fractions, but it had no effect on extracellular-regulated kinase 1/2 activity. Ninety min after R-baclofen treatment, we observed an increase in metabotropic glutamate receptor 5 expression in the frontal cortex, a finding that may shed light on the tolerance observed in human studies with this drug.

CONCLUSIONS:

Our results suggest that treatment via activation of the GABA (GABA receptor subtype B) system warrants further study in patients with FXS.

KEYWORDS:

Fragile X syndrome; R-baclofen; mTOR; protein synthesis; social behavior

PMID:
25820841
PMCID:
PMC4576516
DOI:
10.1093/ijnp/pyv034
[Indexed for MEDLINE]
Free PMC Article

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