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

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.

• Authors: Mei Qin, Tianjian Huang, Michael Kader, Leland Krych, Zengyan Xia, Thomas Burlin, Zachary Zeidler, Tingrui Zhao, Carolyn B Smith
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 18 Issue 9 (Mar 28 2015) ISSN: 1469-5111 [Electronic] England
• PMID: 25820841 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Oxford University Press on behalf of CINP 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Chemical References

• Fmr1 protein, mouse
• GABA-B Receptor Agonists
• Fragile X Mental Retardation Protein
• mTOR protein, mouse
• TOR Serine-Threonine Kinases
• Baclofen

Topics

• Animals
• Baclofen (pharmacology)
• Behavior, Animal (drug effects)
• Disease Models, Animal
• Fragile X Mental Retardation Protein
• Fragile X Syndrome (drug therapy)
• Frontal Lobe (drug effects, metabolism)
• GABA-B Receptor Agonists (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Protein Biosynthesis (drug effects)
• Signal Transduction (drug effects)
• Social Behavior
• TOR Serine-Threonine Kinases (metabolism)