Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Pharmacological Treatments for Fragile X Syndrome Based on Synaptic Dysfunction

Author(s): Michael Telias*

Volume 25, Issue 41, 2019

Page: [4394 - 4404] Pages: 11

DOI: 10.2174/1381612825666191102165206

Price: $65


Background: Fragile X syndrome (FXS) is the most common form of monogenic hereditary cognitive impairment, including intellectual disability, autism, hyperactivity, and epilepsy.

Methods: This article reviews the literature pertaining to the role of synaptic dysfunction in FXS.

Results: In FXS, synaptic dysfunction alters the excitation-inhibition ratio, dysregulating molecular and cellular processes underlying cognition, learning, memory, and social behavior. Decades of research have yielded important hypotheses that could explain, at least in part, the development of these neurological disorders in FXS patients. However, the main goal of translating lab research in animal models to pharmacological treatments in the clinic has been so far largely unsuccessful, leaving FXS a still incurable disease.

Conclusion: In this concise review, we summarize and analyze the main hypotheses proposed to explain synaptic dysregulation in FXS, by reviewing the scientific evidence that led to pharmaceutical clinical trials and their outcome.

Keywords: Synaptic plasticity, fragile X syndrome, autism spectrum disorders, mouse models, animal models, human pluripotent stem cells, pharmacotherapy, clinical trial, drug candidate.

Penagarikano O, Mulle JG, Warren ST. The pathophysiology of fragile X syndrome. Annu Rev Genomics Hum Genet 2007; 8: 109-29.
[] [PMID: 17477822]
Hagerman RJ, Berry-Kravis E, Hazlett HC, et al. Fragile X syndrome. Nat Rev Dis Primers 2017; 3: 17065.
[] [PMID: 28960184]
Chakrabarti L, Davies KE. Fragile X syndrome. Curr Opin Neurol 1997; 10(2): 142-7.
[] [PMID: 9146995]
Verkerk AJ, Pieretti M, Sutcliffe JS, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991; 65(5): 905-14.
[] [PMID: 1710175]
O’Donnell WT, Warren ST. A decade of molecular studies of fragile X syndrome. Annu Rev Neurosci 2002; 25: 315-38.
[] [PMID: 12052912]
Mor-Shaked H, Eiges R. Reevaluation of FMR1 hypermethylation timing in fragile X syndrome. Front Mol Neurosci 2018; 11: 31.
[] [PMID: 29467618]
Ascano M Jr, Mukherjee N, Bandaru P, et al. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature 2012; 492(7429): 382-6.
[] [PMID: 23235829]
Pasciuto E, Bagni C. SnapShot: FMRP mRNA targets and diseases. Cell 2014; 158(6): 1446.
[] [PMID: 25215498]
Kidd SA, Lachiewicz A, Barbouth D, et al. Fragile X syndrome: a review of associated medical problems. Pediatrics 2014; 134(5): 995-1005.
[] [PMID: 25287458]
Kaufmann WE, Kidd SA, Andrews HF, et al. Autism spectrum disorder in fragile X syndrome: cooccurring conditions and current treatment. Pediatrics 2017; 139(Suppl. 3): S194-206.
[] [PMID: 28814540]
Bagni C, Oostra BA. Fragile X syndrome: From protein function to therapy. Am J Med Genet A 2013; 161A(11): 2809-21.
[] [PMID: 24115651]
Fernández E, Rajan N, Bagni C. The FMRP regulon: from targets to disease convergence. Front Neurosci 2013; 7: 191.
[] [PMID: 24167470]
Castrén M, Tervonen T, Kärkkäinen V, et al. Altered differentiation of neural stem cells in fragile X syndrome. Proc Natl Acad Sci USA 2005; 102(49): 17834-9.
[] [PMID: 16314562]
Telias M, Segal M, Ben-Yosef D. Neural differentiation of fragile X human embryonic stem cells reveals abnormal patterns of development despite successful neurogenesis. Dev Biol 2013; 374(1): 32-45.
[] [PMID: 23219959]
Telias M, Mayshar Y, Amit A, Ben-Yosef D. Molecular mechanisms regulating impaired neurogenesis of fragile X syndrome human embryonic stem cells. Stem Cells Dev 2015; 24(20): 2353-65.
[] [PMID: 26393806]
Tian Y, Yang C, Shang S, et al. Loss of FMRP impaired hippocampal long-term plasticity and spatial learning in rats. Front Mol Neurosci 2017; 10: 269.
[] [PMID: 28894415]
Irwin SA, Galvez R, Greenough WT. Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb Cortex 2000; 10(10): 1038-44.
[] [PMID: 11007554]
Segal M, Kreher U, Greenberger V, Braun K. Is fragile X mental retardation protein involved in activity-induced plasticity of dendritic spines? Brain Res 2003; 972(1-2): 9-15.
[] [PMID: 12711073]
Braun K, Segal M. FMRP involvement in formation of synapses among cultured hippocampal neurons. Cereb Cortex 2000; 10(10): 1045-52.
[] [PMID: 11007555]
Bear MF. Therapeutic implications of the mGluR theory of fragile X mental retardation. Genes Brain Behav 2005; 4(6): 393-8.
[] [PMID: 16098137]
Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci 2004; 27(7): 370-7.
[] [PMID: 15219735]
Ribeiro FM, Vieira LB, Pires RG, Olmo RP, Ferguson SS. Metabotropic glutamate receptors and neurodegenerative diseases. Pharmacol Res 2017; 115: 179-91.
[] [PMID: 27872019]
Braat S, D’Hulst C, Heulens I, et al. The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome. Cell Cycle 2015; 14(18): 2985-95.
[] [PMID: 25790165]
D’Hulst C, Kooy RF. The GABAA receptor: a novel target for treatment of fragile X? Trends Neurosci 2007; 30(8): 425-31.
[] [PMID: 17590448]
Telias M, Segal M, Ben-Yosef D. Immature responses to GABA in fragile X neurons derived from human embryonic stem cells. Front Cell Neurosci 2016; 10: 121.
[] [PMID: 27242433]
Telias M, Kuznitsov-Yanovsky L, Segal M, Ben-Yosef D. Functional deficiencies in fragile X neurons derived from human embryonic stem cells. J Neurosci 2015; 35(46): 15295-306.
[] [PMID: 26586818]
Deng PY, Sojka D, Klyachko VA. Abnormal presynaptic short-term plasticity and information processing in a mouse model of fragile X syndrome. J Neurosci 2011; 31(30): 10971-82.
[] [PMID: 21795546]
Deng PY, Rotman Z, Blundon JA, et al. FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels. Neuron 2013; 77(4): 696-711.
[] [PMID: 23439122]
Antoine MW, Langberg T, Schnepel P, Feldman DE. Increased excitation-inhibition ratio stabilizes synapse and circuit excitability in four autism mouse models Neuron 2019; 101(4): 648-61 e4.
Godfraind JM, Reyniers E, De Boulle K, et al. Long-term potentiation in the hippocampus of fragile X knockout mice. Am J Med Genet 1996; 64(2): 246-51.
[<246:AID-AJMG2>3.0.CO;2-S] [PMID: 8844057]
Huber KM, Gallagher SM, Warren ST, Bear MF. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci USA 2002; 99(11): 7746-50.
[] [PMID: 12032354]
Maj C, Minelli A, Giacopuzzi E, Sacchetti E, Gennarelli M. The role of metabotropic glutamate receptor genes in schizophrenia. Curr Neuropharmacol 2016; 14(5): 540-50.
[] [PMID: 27296644]
Todd PK, Mack KJ, Malter JS. The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95. Proc Natl Acad Sci USA 2003; 100(24): 14374-8.
[] [PMID: 14614133]
Antar LN, Afroz R, Dictenberg JB, Carroll RC, Bassell GJ. Metabotropic glutamate receptor activation regulates fragile x mental retardation protein and FMR1 mRNA localization differentially in dendrites and at synapses. J Neurosci 2004; 24(11): 2648-55.
Aschrafi A, Cunningham BA, Edelman GM, Vanderklish PW. The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain. Proc Natl Acad Sci USA 2005; 102(6): 2180-5.
[] [PMID: 15684045]
Desai NS, Casimiro TM, Gruber SM, Vanderklish PW. Early postnatal plasticity in neocortex of Fmr1 knockout mice. J Neurophysiol 2006; 96(4): 1734-45.
[] [PMID: 16823030]
Huang J, Ikeuchi Y, Malumbres M, Bonni AA. Cdh1-APC/FMRP ubiquitin signaling link drives mGluR-dependent synaptic plasticity in the mammalian brain. Neuron 2015; 86(3): 726-39.
[] [PMID: 25913861]
Sourial M, Cheng C, Doering LC. Progress toward therapeutic potential for AFQ056 in fragile X syndrome. J Exp Pharmacol 2013; 5: 45-54.
[PMID: 27186135]
Berry-Kravis E. Mechanism-based treatments in neurodevelopmental disorders: fragile X syndrome. Pediatr Neurol 2014; 50(4): 297-302.
[] [PMID: 24518745]
Baudouin SJ, Gaudias J, Gerharz S, et al. Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism. Science 2012; 338(6103): 128-32.
[] [PMID: 22983708]
Meyza KZ, Blanchard DC. The BTBR mouse model of idiopathic autism - Current view on mechanisms. Neurosci Biobehav Rev 2017; 76(Pt A): 99-110.
Seese RR, Maske AR, Lynch G, Gall CM. Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism. Neuropsychopharmacology 2014; 39(7): 1664-73.
Jeyabalan N, Clement JP. SYNGAP1: mind the gap. Front Cell Neurosci 2016; 10: 32.
[] [PMID: 26912996]
Barnes SA, Wijetunge LS, Jackson AD, et al. Convergence of hippocampal pathophysiology in Syngap+/- and Fmr1-/y Mice. J Neurosci 2015; 35(45): 15073-81.
[] [PMID: 26558778]
Achuta VS, Grym H, Putkonen N, et al. Metabotropic glutamate receptor 5 responses dictate differentiation of neural progenitors to NMDA-responsive cells in fragile X syndrome. Dev Neurobiol 2017; 77(4): 438-53.
[] [PMID: 27411166]
Uzunova G, Hollander E, Shepherd J. The role of ionotropic glutamate receptors in childhood neurodevelopmental disorders: autism spectrum disorders and fragile x syndrome. Curr Neuropharmacol 2014; 12(1): 71-98.
[] [PMID: 24533017]
Li J, Pelletier MR, Perez Velazquez JL, Carlen PL. Reduced cortical synaptic plasticity and GluR1 expression associated with fragile X mental retardation protein deficiency. Mol Cell Neurosci 2002; 19(2): 138-51.
[] [PMID: 11860268]
Hu H, Qin Y, Bochorishvili G, Zhu Y, van Aelst L, Zhu JJ. Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome. J Neurosci 2008; 28(31): 7847-62.
[] [PMID: 18667617]
Pilpel Y, Kolleker A, Berberich S, et al. Synaptic ionotropic glutamate receptors and plasticity are developmentally altered in the CA1 field of Fmr1 knockout mice. J Physiol 2009; 587(Pt 4): 787-804.
[] [PMID: 19103683]
Toft AK, Lundbye CJ, Banke TG. Dysregulated NMDA-receptor signaling inhibits long-term depression in a mouse model of fragile X syndrome. J Neurosci 2016; 36(38): 9817-27.
[] [PMID: 27656021]
Scharkowski F, Frotscher M, Lutz D, Korte M, Michaelsen-Preusse K. Altered connectivity and synapse maturation of the hippocampal mossy fiber pathway in a mouse model of the fragile X syndrome. Cereb Cortex 2018; 28(3): 852-67.
[] [PMID: 28077511]
Achuta VS, Möykkynen T, Peteri UK, et al. Functional changes of AMPA responses in human induced pluripotent stem cell-derived neural progenitors in fragile X syndrome. Sci Signal 2018; 11(513) eaan8784
[] [PMID: 29339535]
Mele M, Leal G, Duarte CB. Role of GABAA R trafficking in the plasticity of inhibitory synapses. J Neurochem 2016; 139(6): 997-1018.
[] [PMID: 27424566]
Fritschy JM, Panzanelli P. GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system. Eur J Neurosci 2014; 39(11): 1845-65.
[] [PMID: 24628861]
Paluszkiewicz SM, Martin BS, Huntsman MM. Fragile X syndrome: the GABAergic system and circuit dysfunction. Dev Neurosci 2011; 33(5): 349-64.
[] [PMID: 21934270]
D’Hulst C, De Geest N, Reeve SP, et al. Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res 2006; 1121(1): 238-45.
[] [PMID: 17046729]
Sabanov V, Braat S, D’Andrea L, et al. Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice. Neuropharmacology 2017; 116: 71-81.
[] [PMID: 28012946]
Zhang N, Peng Z, Tong X, et al. Decreased surface expression of the δ subunit of the GABAA receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome. Exp Neurol 2017; 297: 168-78.
[] [PMID: 28822839]
Olmos-Serrano JL, Paluszkiewicz SM, Martin BS, Kaufmann WE, Corbin JG, Huntsman MM. Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J Neurosci 2010; 30(29): 9929-38.
[] [PMID: 20660275]
D’Hulst C, Heulens I, Brouwer JR, et al. Expression of the GABAergic system in animal models for fragile X syndrome and fragile X associated tremor/ataxia syndrome (FXTAS). Brain Res 2009; 1253: 176-83.
[] [PMID: 19070606]
Silverman JL, Pride MC, Hayes JE, et al. GABAB receptor agonist R-baclofen reverses social deficits and reduces repetitive behavior in two mouse models of autism. Neuropsychopharmacology 2015; 40(9): 2228-39.
Kang JY, Chadchankar J, Vien TN, et al. Deficits in the activity of presynaptic γ-aminobutyric acid type B receptors contribute to altered neuronal excitability in fragile X syndrome. J Biol Chem 2017; 292(16): 6621-32.
[] [PMID: 28213518]
D’Hulst C, Heulens I, Van der Aa N, et al. Positron emission tomography (PET) quantification of GABAA Receptors in the Brain of Fragile X Patients. PLoS One 2015; 10(7) e0131486
[] [PMID: 26222316]
Braat S, Kooy RF. Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials. Neuropharmacology 2015; 88: 48-54.
[] [PMID: 25016041]
Ligsay A, Van Dijck A, Nguyen DV, et al. A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome. J Neurodev Disord 2017; 9(1): 26.
[] [PMID: 28764646]
Cogram P, Deacon RMJ, Warner-Schmidt JL, von Schimmelmann MJ, Abrahams BS, During MJ. Gaboxadol normalizes behavioral abnormalities in a mouse model of fragile X syndrome. Front Behav Neurosci 2019; 13: 141.
[] [PMID: 31293404]
Berry-Kravis E, Hagerman R, Visootsak J, et al. Arbaclofen in fragile X syndrome: results of phase 3 trials. J Neurodev Disord 2017; 9: 3.
[] [PMID: 28616094]
Veenstra-VanderWeele J, Cook EH, King BH, et al. Arbaclofen in children and adolescents with autism spectrum disorder: a randomized, controlled, phase 2 trial. Neuropsychopharmacology 2017; 42(7): 1390-8.
Frye RE. Clinical potential, safety, and tolerability of arbaclofen in the treatment of autism spectrum disorder. Drug Healthc Patient Saf 2014; 6: 69-76.
[] [PMID: 24872724]
Erickson CA, Veenstra-Vanderweele JM, Melmed RD, et al. STX209 (arbaclofen) for autism spectrum disorders: an 8-week open-label study. J Autism Dev Disord 2014; 44(4): 958-64.
[] [PMID: 24272415]
Davenport MH, Schaefer TL, Friedmann KJ, Fitzpatrick SE, Erickson CA. Pharmacotherapy for fragile X syndrome: progress to date. Drugs 2016; 76(4): 431-45.
[] [PMID: 26858239]
Berry-Kravis EM, Lindemann L, Jønch AE, et al. Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome. Nat Rev Drug Discov 2018; 17(4): 280-99.
[] [PMID: 29217836]
Costa L, Spatuzza M, D’Antoni S, et al. Activation of 5-HT7 serotonin receptors reverses metabotropic glutamate receptor-mediated synaptic plasticity in wild-type and Fmr1 knockout mice, a model of fragile X syndrome. Biol Psychiatry 2012; 72(11): 924-33.
[] [PMID: 22817866]
Lim CS, Hoang ET, Viar KE, Stornetta RL, Scott MM, Zhu JJ. Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model. Genes Dev 2014; 28(3): 273-89.
[] [PMID: 24493647]
Costa L, Sardone LM, Lacivita E, Leopoldo M, Ciranna L. Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of fragile X syndrome. Front Behav Neurosci 2015; 9: 65.
[] [PMID: 25814945]
Costa L, Sardone LM, Bonaccorso CM, et al. Activation of serotonin 5-HT7 receptors modulates hippocampal synaptic plasticity by stimulation of adenylate cyclases and rescues learning and behavior in a mouse model of fragile X syndrome. Front Mol Neurosci 2018; 11: 353.
[] [PMID: 30333723]
Greiss Hess L, Fitzpatrick SE, Nguyen DV, et al. A randomized, double-blind, placebo-controlled trial of low-dose sertraline in young children with fragile X syndrome. J Dev Behav Pediatr 2016; 37(8): 619-28.
[] [PMID: 27560971]
AlOlaby RR, Sweha SR, Silva M, et al. Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome. Brain Dev 2017; 39(6): 483-92.
[] [PMID: 28242040]
Maneeton N, Maneeton B, Putthisri S, Suttajit S, Likhitsathian S, Srisurapanont M. Aripiprazole in acute treatment of children and adolescents with autism spectrum disorder: a systematic review and meta-analysis. Neuropsychiatr Dis Treat 2018; 14: 3063-72.
[] [PMID: 30519027]
Bartram LA, Lozano J, Coury DL. Aripiprazole for treating irritability associated with autism spectrum disorders. Expert Opin Pharmacother 2019; 20(12): 1421-7.
[] [PMID: 31180743]
Ghanizadeh A, Tordjman S, Jaafari N. Aripiprazole for treating irritability in children & adolescents with autism: a systematic review. Indian J Med Res 2015; 142(3): 269-75.
[] [PMID: 26458342]
Erickson CA, Stigler KA, Wink LK, et al. A prospective open-label study of aripiprazole in fragile X syndrome. Psychopharmacology (Berl) 2011; 216(1): 85-90.
Sanderson TM, Hogg EL, Collingridge GL, Corrêa SA. Hippocampal metabotropic glutamate receptor long-term depression in health and disease: focus on mitogen-activated protein kinase pathways. J Neurochem 2016; 139(Suppl. 2): 200-14.
[] [PMID: 26923875]
Michalon A, Sidorov M, Ballard TM, et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 2012; 74(1): 49-56.
[] [PMID: 22500629]
Sawicka K, Pyronneau A, Chao M, Bennett MV, Zukin RS. Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice. Proc Natl Acad Sci USA 2016; 113(41): E6290-7.
[] [PMID: 27663742]
Wang X, Snape M, Klann E, et al. Activation of the extracellular signal-regulated kinase pathway contributes to the behavioral deficit of fragile x-syndrome. J Neurochem 2012; 121(4): 672-9.
[] [PMID: 22393900]
Gantois I, Khoutorsky A, Popic J, et al. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat Med 2017; 23(6): 674-7.
[] [PMID: 28504725]
Protic D, Aydin EY, Tassone F, Tan MM, Hagerman RJ, Schneider A. Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin-two cases. Mol Genet Genomic Med 2019; 7(7) e00745
[] [PMID: 31104364]
Yau SY, Chiu C, Vetrici M, Christie BR. Chronic minocycline treatment improves social recognition memory in adult male Fmr1 knockout mice. Behav Brain Res 2016; 312: 77-83.
[] [PMID: 27291517]
Haenfler JM, Skariah G, Rodriguez CM, et al. Targeted reactivation of FMR1 transcription in fragile X syndrome embryonic stem cells. Front Mol Neurosci 2018; 11: 282.
[] [PMID: 30158855]
Yrigollen CM, Davidson BL. CRISPR to the rescue: advances in gene editing for the FMR1 gene. Brain Sci 2019; 9(1) E17
[] [PMID: 30669625]
Li M, Zhao H, Ananiev GE, et al. Establishment of reporter lines for detecting fragile X mental retardation (FMR1) gene reactivation in human neural cells. Stem Cells 2017; 35(1): 158-69.
[] [PMID: 27422057]
Park CY, Halevy T, Lee DR, et al. Reversion of FMR1 methylation and silencing by editing the triplet repeats in fragile X iPSC-derived neurons. Cell Rep 2015; 13(2): 234-41.
[] [PMID: 26440889]
Liu XS, Wu H, Krzisch M, et al. Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell 2018; 172(5): 979.
Gantois I, Pop AS, de Esch CE, et al. Chronic administration of AFQ056/mavoglurant restores social behaviour in Fmr1 knockout mice. Behav Brain Res 2013; 239: 72-9.
[] [PMID: 23142366]
Gomez-Mancilla B, Berry-Kravis E, Hagerman R, et al. Development of mavoglurant and its potential for the treatment of fragile X syndrome. Expert Opin Investig Drugs 2014; 23(1): 125-34.
[] [PMID: 24251408]
Pop AS, Levenga J, de Esch CE, et al. Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/mavoglurant. Psychopharmacology (Berl) 2014; 231(6): 1227-35.
[] [PMID: 23254376]
Vranesic I, Ofner S, Flor PJ, et al. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. Bioorg Med Chem 2014; 22(21): 5790-803.
[] [PMID: 25316499]
Scharf SH, Jaeschke G, Wettstein JG, Lindemann L. Metabotropic glutamate receptor 5 as drug target for fragile X syndrome. Curr Opin Pharmacol 2015; 20: 124-34.
[] [PMID: 25488569]
Bailey DB Jr, Berry-Kravis E, Wheeler A, et al. Mavoglurant in adolescents with fragile X syndrome: analysis of clinical global impression-improvement source data from a double-blind therapeutic study followed by an open-label, long-term extension study. J Neurodev Disord 2016; 8: 1.
[] [PMID: 26855682]
Berry-Kravis E, Des Portes V, Hagerman R, et al. Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med 2016; 8(321) 321ra5
[] [PMID: 26764156]
Dy ABC, Tassone F, Eldeeb M, Salcedo-Arellano MJ, Tartaglia N, Hagerman R. Metformin as targeted treatment in fragile X syndrome. Clin Genet 2018; 93(2): 216-22.
[] [PMID: 28436599]
Zerbi V, Markicevic M, Gasparini F, Schroeter A, Rudin M, Wenderoth N. Inhibiting mGluR5 activity by AFQ056/mavoglurant rescues circuit-specific functional connectivity in Fmr1 knockout mice. Neuroimage 2019; 191: 392-402.
[] [PMID: 30807820]
Youssef EA, Berry-Kravis E, Czech C, et al. Effect of the mGluR5-NAM basimglurant on behavior in adolescents and adults with fragile X syndrome in a randomized, double-blind, placebo-controlled trial: FragXis phase 2 results. Neuropsychopharmacology 2018; 43(3): 503-12.
Jaeschke G, Kolczewski S, Spooren W, et al. Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases. J Med Chem 2015; 58(3): 1358-71.
[] [PMID: 25565255]
Lindemann L, Porter RH, Scharf SH, et al. Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression. J Pharmacol Exp Ther 2015; 353(1): 213-33.
[] [PMID: 25665805]
Fu T, Zheng G, Tu G, et al. Exploring the binding mechanism of metabotropic glutamate receptor 5 negative allosteric modulators in clinical trials by molecular dynamics simulations. ACS Chem Neurosci 2018; 9(6): 1492-502.
[] [PMID: 29522307]
Berry-Kravis E, Hessl D, Coffey S, et al. A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet 2009; 46(4): 266-71.
[] [PMID: 19126569]
Wang GX, Smith SJ, Mourrain P. Fmr1 KO and fenobam treatment differentially impact distinct synapse populations of mouse neocortex. Neuron 2014; 84(6): 1273-86.
[] [PMID: 25521380]
Aguilar-Valles A, Matta-Camacho E, Khoutorsky A, et al. Inhibition of group I metabotropic glutamate receptors reverses autistic-like phenotypes caused by deficiency of the translation repressor eIF4E binding protein 2. J Neurosci 2015; 35(31): 11125-32.
[] [PMID: 26245973]
LaCrosse AL, Taylor SB, Nemirovsky NE, Gass JT, Olive MF. mGluR5 positive and negative allosteric modulators differentially affect dendritic spine density and morphology in the prefrontal cortex. CNS Neurol Disord Drug Targets 2015; 14(4): 476-85.
[] [PMID: 25921744]
Berry-Kravis E, Krause SE, Block SS, et al. Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial. J Child Adolesc Psychopharmacol 2006; 16(5): 525-40.
[] [PMID: 17069542]
Lozano R, Martinez-Cerdeno V, Hagerman RJ. Advances in the understanding of the gabaergic neurobiology of FMR1 expanded alleles leading to targeted treatments for fragile X spectrum disorder. Curr Pharm Des 2015; 21(34): 4972-9.
[] [PMID: 26365141]
Heulens I, D’Hulst C, Van Dam D, De Deyn PP, Kooy RF. Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model. Behav Brain Res 2012; 229(1): 244-9.
[] [PMID: 22285772]
Martin BS, Corbin JG, Huntsman MM. Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala. J Neurophysiol 2014; 112(4): 890-902.
[] [PMID: 24848467]
Olmos-Serrano JL, Corbin JG, Burns MP. The GABA(A) receptor agonist THIP ameliorates specific behavioral deficits in the mouse model of fragile X syndrome. Dev Neurosci 2011; 33(5): 395-403.
[] [PMID: 22067669]
Zeidler S, Pop AS, Jaafar IA, et al. Paradoxical effect of baclofen on social behavior in the fragile X syndrome mouse model. Brain Behav 2018; 8(6) e00991
[] [PMID: 29785777]
Sinclair D, Featherstone R, Naschek M, et al. GABA-B Agonist baclofen normalizes auditory-evoked neural oscillations and behavioral deficits in the Fmr1 knockout mouse model of fragile X syndrome. eNeuro 2017; 4(1): pii: ENEURO.0380-16.2017.
[] [PMID: 28451631]
Wahlstrom-Helgren S, Klyachko VA. GABAB receptor-mediated feed-forward circuit dysfunction in the mouse model of fragile X syndrome. J Physiol 2015; 593(22): 5009-24.
[] [PMID: 26282581]
Qin M, Huang T, Kader M, et al. R-baclofen reverses a social behavior deficit and elevated protein synthesis in a mouse model of fragile X syndrome. Int J Neuropsychopharmacol 2015; 18(9) pyv034
[] [PMID: 25820841]
Henderson C, Wijetunge L, Kinoshita MN, et al. Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci Transl Med 2012; 4(152) 152ra128
[] [PMID: 22993295]
Berry-Kravis EM, Hessl D, Rathmell B, et al. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci Transl Med 2012; 4(152) 152ra127
[] [PMID: 22993294]
Neuhofer D, Lassalle O, Manzoni OJ. Muscarinic M1 receptor modulation of synaptic plasticity in nucleus accumbens of wild-type and fragile X mice. ACS Chem Neurosci 2018; 9(9): 2233-40.
[] [PMID: 29486555]
Qiu G, Chen S, Guo J, Wu J, Yi YH. Alpha-asarone improves striatal cholinergic function and locomotor hyperactivity in Fmr1 knockout mice. Behav Brain Res 2016; 312: 212-8.
[] [PMID: 27316341]
Scremin OU, Roch M, Norman KM, Djazayeri S, Liu YY. Brain acetylcholine and choline concentrations and dynamics in a murine model of the fragile X syndrome: age, sex and region-specific changes. Neuroscience 2015; 301: 520-8.
[] [PMID: 26117713]
Sahu JK, Gulati S, Sapra S, et al. Effectiveness and safety of donepezil in boys with fragile X syndrome: a double-blind, randomized, controlled pilot study. J Child Neurol 2013; 28(5): 570-5.
[] [PMID: 22752489]
Bruno JL, Hosseini SH, Lightbody AA, Manchanda MK, Reiss AL. Brain circuitry, behavior, and cognition: a randomized placebo-controlled trial of donepezil in fragile X syndrome. J Psychopharmacol (Oxford) 2019; 33(8): 975-85.
[] [PMID: 31264943]
Xu ZH, Yang Q, Ma L, et al. Deficits in LTP induction by 5-HT2A receptor antagonist in a mouse model for fragile X syndrome. PLoS One 2012; 7(10) e48741
[] [PMID: 23119095]
Hessl D, Tassone F, Cordeiro L, et al. Brief report: aggression and stereotypic behavior in males with fragile X syndrome--moderating secondary genes in a “single gene” disorder. J Autism Dev Disord 2008; 38(1): 184-9.
[] [PMID: 17340199]
Hanson AC, Hagerman RJ. Serotonin dysregulation in Fragile X syndrome: implications for treatment. Intractable Rare Dis Res 2014; 3(4): 110-7.
[] [PMID: 25606361]
Indah Winarni T, Chonchaiya W, Adams E, et al. Sertraline may improve language developmental trajectory in young children with fragile X syndrome: a retrospective chart review. Autism Res Treat 2012; 2012 104317
[] [PMID: 22934167]
Wang W, Cox BM, Jia Y, et al. Treating a novel plasticity defect rescues episodic memory in fragile X model mice. Mol Psychiatry 2018; 23(8): 1798-806.
[] [PMID: 29133950]
Gomis-González M, Busquets-Garcia A, Matute C, Maldonado R, Mato S, Ozaita A. Possible therapeutic doses of cannabinoid type 1 receptor antagonist reverses key alterations in fragile X syndrome mouse model. Genes (Basel) 2016; 7(9) E56
[] [PMID: 27589806]
Busquets-Garcia A, Gomis-González M, Guegan T, et al. Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat Med 2013; 19(5): 603-7.
[] [PMID: 23542787]
Straiker A, Min KT, Mackie K. Fmr1 deletion enhances and ultimately desensitizes CB(1) signaling in autaptic hippocampal neurons. Neurobiol Dis 2013; 56: 1-5.
[] [PMID: 23578490]
Tang AH, Alger BE. Homer protein-metabotropic glutamate receptor binding regulates endocannabinoid signaling and affects hyperexcitability in a mouse model of fragile X syndrome. J Neurosci 2015; 35(9): 3938-45.
[] [PMID: 25740522]
Qin M, Zeidler Z, Moulton K, Krych L, Xia Z, Smith CB. Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome. Behav Brain Res 2015; 291: 164-71.
[] [PMID: 25979787]
Schaefer TL, Davenport MH, Grainger LM, et al. Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety. J Neurodev Disord 2017; 9: 6.
[] [PMID: 28616095]
Erickson CA, Mullett JE, McDougle CJ. Brief report: acamprosate in fragile X syndrome. J Autism Dev Disord 2010; 40(11): 1412-6.
[] [PMID: 20213249]
Erickson CA, Wink LK, Ray B, et al. Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome. Psychopharmacology (Berl) 2013; 228(1): 75-84.
[] [PMID: 23436129]
Fish EW, Krouse MC, Stringfield SJ, Diberto JF, Robinson JE, Malanga CJ. Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome. PLoS One 2013; 8(10) e77896
[] [PMID: 24205018]
Erickson CA, Weng N, Weiler IJ, et al. Open-label riluzole in fragile X syndrome. Brain Res 2011; 1380: 264-70.
[] [PMID: 21059347]
Manor I, Newcorn JH, Faraone SV, Adler LA. Efficacy of metadoxine extended release in patients with predominantly inattentive subtype attention-deficit/hyperactivity disorder. Postgrad Med 2013; 125(4): 181-90.
[] [PMID: 23933905]
Manor I, Ben-Hayun R, Aharon-Peretz J, et al. A randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy, safety, and tolerability of extended-release metadoxine in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry 2012; 73(12): 1517-23.
[] [PMID: 23290324]
Bilousova TV, Dansie L, Ngo M, et al. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet 2009; 46(2): 94-102.
[] [PMID: 18835858]
Rotschafer SE, Trujillo MS, Dansie LE, Ethell IM, Razak KA. Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of fragile X syndrome. Brain Res 2012; 1439: 7-14.
[] [PMID: 22265702]
Dziembowska M, Pretto DI, Janusz A, et al. High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Am J Med Genet A 2013; 161A(8): 1897-903.
[] [PMID: 23824974]
Dansie LE, Phommahaxay K, Okusanya AG, et al. Long-lasting effects of minocycline on behavior in young but not adult Fragile X mice. Neuroscience 2013; 246: 186-98.
[] [PMID: 23660195]
Yau SY, Bettio L, Vetrici M, et al. Chronic minocycline treatment improves hippocampal neuronal structure, NMDA receptor function, and memory processing in Fmr1 knockout mice. Neurobiol Dis 2018; 113: 11-22.
[] [PMID: 29367010]
Toledo MA, Wen TH, Binder DK, Ethell IM, Razak KA. Reversal of ultrasonic vocalization deficits in a mouse model of Fragile X syndrome with minocycline treatment or genetic reduction of MMP-9. Behav Brain Res 2019; 372 112068
[] [PMID: 31271818]
Paribello C, Tao L, Folino A, et al. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol 2010; 10: 91.
[] [PMID: 20937127]
Utari A, Chonchaiya W, Rivera SM, et al. Side effects of minocycline treatment in patients with fragile X syndrome and exploration of outcome measures. Am J Intellect Dev Disabil 2010; 115(5): 433-43.
[] [PMID: 20687826]
Siller SS, Broadie K. Matrix metalloproteinases and minocycline: therapeutic avenues for fragile X syndrome. Neural Plast 2012; 2012 124548
[] [PMID: 22685676]
Leigh MJ, Nguyen DV, Mu Y, et al. A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile X syndrome. J Dev Behav Pediatr 2013; 34(3): 147-55.
[] [PMID: 23572165]
Schneider A, Leigh MJ, Adams P, et al. Electrocortical changes associated with minocycline treatment in fragile X syndrome. J Psychopharmacol (Oxford) 2013; 27(10): 956-63.
[] [PMID: 23981511]
Muscas M, Louros SR, Osterweil EK. Lovastatin, not Simvastatin, Corrects Core Phenotypes in the Fragile X Mouse Model. eNeuro 2019; 6(3): pii: ENEURO.0097-19.2019.
[] [PMID: 31147392]
Asiminas A, Jackson AD, Louros SR, et al. Sustained correction of associative learning deficits after brief, early treatment in a rat model of fragile X syndrome. Sci Transl Med 2019; 11(494) eaao0498
[] [PMID: 31142675]
Osterweil EK, Chuang SC, Chubykin AA, et al. Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 2013; 77(2): 243-50.
[] [PMID: 23352161]
Glaze DG, Neul JL, Kaufmann WE, et al. Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology 2019; 92(16): e1912-25.
[] [PMID: 30918097]
Gantois I, Popic J, Khoutorsky A, Sonenberg N. Metformin for treatment of fragile X syndrome and other neurological disorders. Annu Rev Med 2019; 70: 167-81.
[] [PMID: 30365357]
Biag HMB, Potter LA, Wilkins V, et al. Metformin treatment in young children with fragile X syndrome. Mol Genet Genomic Med 2019; 7(11) e956
Gurney ME, Cogram P, Deacon RM, Rex C, Tranfaglia M. Multiple behavior phenotypes of the fragile-X syndrome mouse model respond to chronic inhibition of phosphodiesterase-4D (PDE4D). Sci Rep 2017; 7(1): 14653.
[] [PMID: 29116166]
Gurney ME, Nugent RA, Mo X, et al. Design and synthesis of selective phosphodiesterase 4D (PDE4D) allosteric inhibitors for the treatment of fragile X syndrome and other brain disorders. J Med Chem 2019; 62(10): 4884-901.
[] [PMID: 31013090]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy