title: Targeting the endocannabinoid system in the treatment of fragile X syndrome.
abstract: Fragile X syndrome (FXS), the most common monogenic cause of inherited intellectual disability and autism, is caused by the silencing of the FMR1 gene, leading to the loss of fragile X mental retardation protein (FMRP), a synaptically expressed RNA-binding protein regulating translation. The Fmr1 knockout model recapitulates the main traits of the disease. Uncontrolled activity of metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) signaling seem crucial in the pathology of this disease. The endocannabinoid system (ECS) is a key modulator of synaptic plasticity, cognitive performance, anxiety, nociception and seizure susceptibility, all of which are affected in FXS. The cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) are activated by phospholipid-derived endocannabinoids, and CB1R-driven long-term regulation of synaptic strength, as a consequence of mGluR5 activation, is altered in several brain areas of Fmr1 knockout mice. We found that CB1R blockade in male Fmr1 knockout (Fmr1(-/y)) mice through pharmacological and genetic approaches normalized cognitive impairment, nociceptive desensitization, susceptibility to audiogenic seizures, overactivated mTOR signaling and altered spine morphology, whereas pharmacological blockade of CB2R normalized anxiolytic-like behavior. Some of these traits were also reversed by pharmacological inhibition of mTOR or mGluR5. Thus, blockade of ECS is a potential therapeutic approach to normalize specific alterations in FXS.
authors.affiliation: Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Busquets-Garcia
authors.forename: Maria
authors.initials: M
authors.lastname: Gomis-González
authors.forename: Thomas
authors.initials: T
authors.lastname: Guegan
authors.forename: Carmen
authors.initials: C
authors.lastname: Agustín-Pavón
authors.forename: Antoni
authors.initials: A
authors.lastname: Pastor
authors.forename: Susana
authors.initials: S
authors.lastname: Mato
authors.forename: Alberto
authors.initials: A
authors.lastname: Pérez-Samartín
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
authors.forename: Rafael
authors.initials: R
authors.lastname: de la Torre
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Andrés
authors.initials: A
authors.lastname: Ozaita
mesh_terms: D000818:Animals; D003071:Cognition; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D005600:Fragile X Syndrome / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D010880:Piperidines / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D016601:RNA-Binding Proteins / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D000077285:Rimonabant
chemical_list: D063388:Endocannabinoids; C578936:Grm5 protein, mouse; D010880:Piperidines; D011720:Pyrazoles; D016601:RNA-Binding Proteins; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D000077285:Rimonabant
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