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

Henderson, Christina; Wijetunge, Lasani; Kinoshita, Mika Nakamoto; Shumway, Matthew; Hammond, Rebecca S.; Postma, Friso R.; Brynczka, Christopher; Rush, Roger; Thomas, Alexia; Paylor, Richard; Warren, Stephen T.; Vanderklish, Peter W.; Kind, Peter C.; Carpenter, Randall L.; Bear, Mark F.; Healy, Aileen M.

doi:10.1126/scitranslmed.3004218

Cited by 249Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchDown syndrome and intellectual disability research

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

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Henderson, Christina, Wijetunge, Lasani, Kinoshita, Mika Nakamoto, Shumway, Matthew, Hammond, Rebecca S., Postma, Friso R., Brynczka, Christopher, Rush, Roger +8 more·2012·Science Translational Medicine

DOI 10.1126/scitranslmed.3004218PMC PMC8826584

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Abstract

Pharmacological activation of the GABA B receptor with arbaclofen in a mouse model of fragile X syndrome corrects neuronal defects associated with the disease.

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Crossref · 10.1126/scitranslmed.3004218

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Activation of the GABA B receptor by arbaclofen decreased mRNA translation in the cortex of fragile X mice and corrected increased spine density.
“Activation of the GABA B receptor by arbaclofen decreased mRNA translation in the cortex of fragile X mice and corrected the increased spine density 78 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [78]
GABAB agonists such as baclofen or arbaclofen correct excessive protein synthesis and multiple phenotypes in Fmr1-knockout mice.
“Administration of GABAB agonists, such as baclofen or arbaclofen, corrects exacerbated protein synthesis and multiple phenotypes in Fmr1-KO mice37–39.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [37]
In Fmr1-knockout mice, mGluR antagonists, GABAB agonists, and gene reinstatement beginning in young adult or adult mice can fully correct most behavioural, physiological, biochemical, and neuroanatomical alterations.
“treatment with mGluR antagonists (mavoglurant) and GABAB agonists (arbaclofen), as well as gene reinstatement in Fmr1-KO mice starting in young adult or adult mice, can fully correct most behavioural, physiological, biochemical and neuroanatomical alterations30,32,37.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [37]
No human data are available for spinocerebellar ataxia type 1 because no suitable drug for clinical trials exists.
“No human data are available for SCA1 in the absence of a drug suitable for clinical trials30,32,37.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [37]
Arbaclofen has rescued behavioral deficits including social deficits in mouse models of idiopathic ASD, deletion of 16p11.2, and FXS.
“For many subtypes of ASD, there is a GABAB deficit and arbaclofen has rescued the behavioral deficits including social deficits in the mouse models of idiopathic ASD [127], deletion of 16p11.2 [128], and FXS [129].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [129]

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Thomas, A. M., Bui, N., Perkins, J. R., Yuva‐Paylor, L. A., & Paylor, R. E. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2375-4 · Cited by 99 · see citing works
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Fragile X Mental Retardation Protein FMRP Binds mRNAs in the Nucleus
Kim, M., Bellini, M., & Ceman, S. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01377-08 · Cited by 98 · see citing works
Social behavior in Fmr1 knockout mice carrying a human FMR1 transgene.
Spencer, C. M., Graham, D. F., Yuva-Paylor, L. A., Nelson, D. L., & Paylor, R. (2008) · Behavioral Neuroscience · doi:10.1037/0735-7044.122.3.710 · Cited by 91 · see citing works
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Altered maturation of the primary somatosensory cortex in a mouse model of fragile X syndrome
Till, S. M., Wijetunge, L. S., Seidel, V. G., Harlow, E., Wright, A. K., Bagni, C., Contractor, A., Gillingwater, T. H., & Kind, P. C. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds030 · Cited by 91 · see citing works
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GABAB-Mediated Presynaptic Inhibition of Excitatory Transmission and Synaptic Vesicle Dynamics in Cultured Hippocampal Neurons
Isaacson, J. S., & Hille, B. (1997) · Neuron · doi:10.1016/s0896-6273(01)80053-2 · Cited by 88 · see citing works
Fragile X Syndrome: Assessment and Treatment Implications
Reiss, A. L., & Hall, S. S. (2007) · Child and Adolescent Psychiatric Clinics of North America · doi:10.1016/j.chc.2007.03.001 · Cited by 88 · see citing works
Synaptogenesis in the developing mouse visual cortex
Ming-shan, L., Cui, Z., Niu, Y., Liu, B., Fan, W., Yu, D., & Deng, J. (2009) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2009.08.028 · Cited by 80 · see citing works
Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome
Su, T., Fan, H.-X., Jiang, T., Sun, W.-W., Den, W.-Y., Gao, M.-M., Chen, S.-Q., Zhao, Q.-H., & Yi, Y.-H. (2011) · Psychopharmacology · doi:10.1007/s00213-010-2130-2 · Cited by 76 · see citing works
mGluR5 Regulates Glutamate-Dependent Development of the Mouse Somatosensory Cortex
Wijetunge, L. S., Till, S. M., Gillingwater, T. H., Ingham, C. A., & Kind, P. C. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2600-08.2008 · Cited by 74 · see citing works
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Genetic reduction of group 1 metabotropic glutamate receptors alters select behaviors in a mouse model for fragile X syndrome
Thomas, A. M., Bui, N., Graham, D. F., Perkins, J. R., Yuva‐Paylor, L. A., & Paylor, R. E. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.04.049 · Cited by 74 · see citing works
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Loss of the Fragile X Mental Retardation Protein Decouples Metabotropic Glutamate Receptor Dependent Priming of Long-Term Potentiation From Protein Synthesis
Auerbach, B. D., & Bear, M. F. (2010) · Journal of Neurophysiology · doi:10.1152/jn.00449.2010 · Cited by 71 · see citing works
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Which Comes First in Fragile X Syndrome, Dendritic Spine Dysgenesis or Defects in Circuit Plasticity?
Portera‐Cailliau, C. (2011) · The Neuroscientist · doi:10.1177/1073858410395322 · Cited by 68 · see citing works
Developmental regulation of spine and filopodial motility in primary visual cortex: Reduced effects of activity and sensory deprivation
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Aberrant Brain Activation During Gaze Processing in Boys With Fragile X Syndrome
Watson, C., Hoeft, F., Garrett, A. S., Hall, S. S., & Reiss, A. L. (2008) · Archives of General Psychiatry · doi:10.1001/archpsyc.65.11.1315 · Cited by 65 · see citing works
Differential Trafficking of AMPA and NMDA Receptors during Long-Term Potentiation in Awake Adult Animals
Williams, J. M., Guévremont, D., Mason‐Parker, S. E., Luxmanan, C., Tate, W. P., & Abraham, W. C. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2348-07.2007 · Cited by 64 · see citing works
Modulation of behavioral phenotypes by a muscarinic M1 antagonist in a mouse model of fragile X syndrome
Veeraragavan, S., Bui, N., Perkins, J. R., Yuva‐Paylor, L. A., Carpenter, R. L., & Paylor, R. E. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2276-6 · Cited by 60 · see citing works
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Genetic reduction of muscarinic M4 receptor modulates analgesic response and acoustic startle response in a mouse model of fragile X syndrome (FXS)
Veeraragavan, S., Graham, D. F., Bui, N., Yuva‐Paylor, L. A., Wess, J., & Paylor, R. E. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.11.018 · Cited by 57 · see citing works
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Receptor‐specific inhibition of GABAB‐activated K+ currents by muscarinic and metabotropic glutamate receptors in immature rat hippocampus
Sohn, J., Lee, D., Cho, H., Lim, W., Shin, H., Lee, S., & Ho, W. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2006.125914 · Cited by 52 · see citing works
Subchronic Administration and Combination Metabotropic Glutamate and GABAB Receptor Drug Therapy in Fragile X Syndrome
Pacey, L. K. K., Tharmalingam, S., & Hampson, D. R. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.183327 · Cited by 52 · see citing works
Tolerance to the effects of baclofen and gamma-butyrolactone on locomotor activity and dopaminergic neurons in the mouse.
Gianutsos, G., & Moore, K. E. (1978) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)31488-6 · Cited by 47 · see citing works
Fmrp is required for the establishment of the startle response during the critical period of auditory development
Yun, S., Platholi, J., Flaherty, M. S., Fu, W., Kottmann, A. H., & Tóth, M. (2006) · Brain Research · doi:10.1016/j.brainres.2006.06.086 · Cited by 44 · see citing works
Simple pharmacological test battery to assess efficacy and side effect profile of centrally acting muscle relaxant drugs
Farkas, S., Berzsenyi, P., Kárpáti, E., Kocsis, P., & Tarnawa, I. (2005) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/j.vascn.2004.11.005 · Cited by 41 · see citing works
The modulation of fragile X behaviors by the muscarinic M4 antagonist, tropicamide.
Veeraragavan, S., Bui, N., Perkins, J. R., Yuva‐Paylor, L. A., & Paylor, R. E. (2011) · Behavioral Neuroscience · doi:10.1037/a0025202 · Cited by 34 · see citing works
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Fragile X syndrome
Hagerman, R. J., Berry-Kravis, E., Hazlett, H. C., Bailey, D. B., Moine, H., Kooy, R. F., Tassone, F., Gantois, I., Sonenberg, N., Mandel, J. L., et al. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.65 · Cited by 838 · see citing works
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mTOR complexes in neurodevelopmental and neuropsychiatric disorders
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Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial
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Germline Chd8 haploinsufficiency alters brain development in mouse
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Excitatory/inhibitory imbalance in autism spectrum disorders: Implications for interventions and therapeutics
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Modeling fragile X syndrome in the Fmr1 knockout mouse
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Progress toward treatments for synaptic defects in autism
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GABAB Receptor Agonist R-Baclofen Reverses Social Deficits and Reduces Repetitive Behavior in Two Mouse Models of Autism
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The Unstable Repeats—Three Evolving Faces of Neurological Disease
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Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome
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Genetic Effects on Cerebellar Structure Across Mouse Models of Autism Using a Magnetic Resonance Imaging Atlas
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Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial
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Synaptic proteins and receptors defects in autism spectrum disorders
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Cognitive Dysfunctions in Intellectual Disabilities: The Contributions of the Ras-MAPK and PI3K-AKT-mTOR Pathways
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Next-Generation Treatments for Mental Disorders
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Fragile X targeted pharmacotherapy: lessons learned and future directions
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Role of GABAB receptors in learning and memory and neurological disorders
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Pax6-Dependent Cortical Glutamatergic Neuronal Differentiation Regulates Autism-Like Behavior in Prenatally Valproic Acid-Exposed Rat Offspring
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A framework for the investigation of rare genetic disorders in neuropsychiatry
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STX209 (Arbaclofen) for Autism Spectrum Disorders: An 8-Week Open-Label Study
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Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice
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Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition
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Of Men and Mice: Modeling the Fragile X Syndrome
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Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: a parallel mouse and human analysis
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The FMRP regulon: from targets to disease convergence
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Drug discovery for autism spectrum disorder: challenges and opportunities
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Autism spectrum disorders
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Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome
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Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back
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Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome
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Channelopathies in fragile X syndrome
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Fragile X syndrome: From protein function to therapy
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Increased aperiodic gamma power in young boys with Fragile X Syndrome is associated with better language ability
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Delayed myelination in a mouse model of fragile X syndrome
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Prenatal stress and inhibitory neuron systems: implications for neuropsychiatric disorders
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Neural Mechanisms Underlying Repetitive Behaviors in Rodent Models of Autism Spectrum Disorders
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R-Baclofen reverses cognitive deficits and improves social interactions in two lines of 16p11.2 deletion mice
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The genetic landscape of autism spectrum disorders
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Revitalizing Psychiatric Therapeutics
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Impaired activity-dependent neural circuit assembly and refinement in autism spectrum disorder genetic models
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GABA receptor subunit distribution and FMRP–mGluR5 signaling abnormalities in the cerebellum of subjects with schizophrenia, mood disorders, and autism
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Impairments in dendrite morphogenesis as etiology for neurodevelopmental disorders and implications for therapeutic treatments
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GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in theFmr1Knockout Mouse Model of Fragile X Syndrome
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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, P. W., Kind, P. C., Carpenter, R. L., Bear, M. F., & Healy, A. M.
Affiliations: Seaside Therapeutics (United States) (US)
University of Edinburgh (GB)
Emory University (US)
Baylor College of Medicine (US)
Scripps Research Institute (US)
Massachusetts Institute of Technology (US)
Corresponding author: Healy, Aileen M.
ORCID: Postma, Friso R.
Rush, Roger
Warren, Stephen T.
Vanderklish, Peter W.
Kind, Peter C.
Bear, Mark F.
Venue: Science Translational Medicine
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2012-09-19
Volume: 4
Issue: 152
Pages: 152ra128-152ra128
ISSN: 1946-6234 (ISSN-L)
1946-6242
DOI: 10.1126/scitranslmed.3004218
PMC: PMC8826584
OpenAlex: W2096270532
Cited by: 249
References: 102
Citations by year: 2026: 7 · 2025: 9 · 2024: 9 · 2023: 8 · 2022: 20 · 2021: 21 · 2020: 10 · 2019: 20 · 2018: 8 · 2017: 32 · 2016: 14 · 2015: 25 · 2014: 24 · 2013: 31 · 2012: 11
FWCI: 17.48
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Science Translational Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 24064, HD020521, R01HD020521, P30HD024064, R37HD020521)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Keywords: fragile X syndrome, GABAB receptors, baclofen, Fmr1 knockout mice, FMRP, synaptic protein synthesis, dendritic spine morphology, AMPA receptor internalization, mRNA translation, synaptic dysfunction, intellectual disability, autism spectrum disorder, hippocampus
MeSH terms: Animals, Baclofen, Behavior, Animal, Disease Models, Animal, Fragile X Syndrome, Hippocampus, Male, Phenotype, Polyribosomes, Seizures, Synapses, Protein Biosynthesis, Receptors, GABA-B, Receptors, AMPA, Mice, Knockout, Protein Transport, Dendritic Spines, Mice, Fragile X Messenger Ribonucleoprotein 1, GABA-B Receptor Agonists, Drinking Water

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

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