We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Targeting the endocannabinoid system in the treatment of fragile X syndrome.
- Authors
Busquets-Garcia, Arnau; Gomis-González, Maria; Guegan, Thomas; Agustín-Pavón, Carmen; Pastor, Antoni; Mato, Susana; Pérez-Samartín, Alberto; Matute, Carlos; de la Torre, Rafael; Dierssen, Mara; Maldonado, Rafael; Ozaita, Andrés
- 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.
- Subjects
FRAGILE X syndrome; CANNABINOIDS; INTELLECTUAL disabilities; AUTISM; CARRIER proteins; GLUTAMATE receptors; RAPAMYCIN; PHOSPHOLIPIDS; THERAPEUTICS
- Publication
Nature Medicine, 2013, Vol 19, Issue 5, p603
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.3127