Reversal of Disease-Related Pathologies in the Fragile X Mouse Model by Selective Activation of GABA(B) Receptors with Arbaclofen

• Type of Material: Article
• Authors: Stephen Warren, Emory University; Christina Henderson, Seaside Therapeutics Inc; Lasani Wijetunge, University of Edinburgh; Mika Nakamoto Kinoshita, Emory University; Matthew Shumway, Seaside Therapeutics Inc; Rebecca S Hammond, Seaside Therapeutics Inc; Frisco R Postma, Seaside Therapeutics Inc; Christopher Brynczka, Seaside Therapeutics Inc; Roger Rush, Seaside Therapeutics Inc; Alexia Thomas, Baylor College of Medicine; Richard Paylor, Baylor College of Medicine; Peter W Vanderklish, Scripps Research Institute; Peter C Kind, University of Edinburgh; Randall L Carpenter, Seaside Therapeutics Inc; Mark F Bear, Massachusetts Institute of Technology; Aileen M Healy, Seaside Therapeutics Inc
• Language: English
• Date: 2012-09-19
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012, American Association for the Advancement of Science.
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.3004218
• Title of Journal or Parent Work: SCIENCE TRANSLATIONAL MEDICINE
• Volume: 4
• Issue: 152
• Start Page: 152ra128
• End Page: 152ra128
• Grant/Funding Information: This work was supported in part by Seaside Therapeutics, NIH grants HD020521 and HD24064 to S.T.W., and Medical Research Council grant G0601584 to P.C.K.
• Keywords: DENDRITIC SPINES; STARTLE RESPONSE; Life Sciences & Biomedicine; Science & Technology; METABOTROPIC GLUTAMATE RECEPTORS; MENTAL-RETARDATION PROTEIN; Medicine, Research & Experimental; LONG-TERM POTENTIATION; PRIMARY SOMATOSENSORY CORTEX; CEREBRAL-CORTEX; Research & Experimental Medicine; AUTISTIC BEHAVIOR; PYRAMIDAL NEURONS; Cell Biology; GENETIC REDUCTION

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 (GABAB) 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 GABAB 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 GABAB 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.