Reversal of Disease-Related Pathologies in the Fragile X Mouse Model by Selective Activation of GABA B Receptors with Arbaclofen
| Autor: | Peter C. Kind, Peter W. Vanderklish, Richard Paylor, Friso R. Postma, Mika Nakamoto Kinoshita, Mark F. Bear, Christopher Brynczka, Alexia M. Thomas, Lasani S. Wijetunge, Christina Henderson, Rebecca S. Hammond, Matthew Shumway, Stephen T. Warren, Roger Rush, Aileen M. Healy, Randall L. Carpenter |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Baclofen congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Dendritic spine Dendritic Spines AMPA receptor GABAB receptor Biology Hippocampus Article Fragile X Mental Retardation Protein Mice Seizures Internal medicine medicine Animals Receptors AMPA Receptor Psychiatry Mice Knockout Behavior Animal Drinking Water Long-term potentiation General Medicine medicine.disease FMR1 Fragile X syndrome Disease Models Animal Protein Transport Phenotype Endocrinology Receptors GABA-B Metabotropic glutamate receptor Fragile X Syndrome GABA-B Receptor Agonists Polyribosomes Protein Biosynthesis Synapses |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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