Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability. The cognitive deficits in the mouse model for this disorder, the Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mouse, have been restored by different pharmacological approaches, among those the blockade of cannabinoid type 1 (CB1) receptor. In this regard, our previous study showed that the CB1 receptor antagonist/inverse agonist rimonabant normalized a number of core features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects. In this study we show, by using electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg) manage to normalize metabotropic glutamate receptor dependent long-term depression (mGluR-LTD). In addition, low doses of rimonabant (from 0.01 mg/kg) equally normalized the cognitive deficit in the mouse model of FXS. These doses of rimonabant were from 30 to 300 times lower than those required to reduce body weight in rodents and to presumably produce adverse effects in humans. Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in preventing the novel object-recognition memory deficit in Fmr1 KO mice. These data further support targeting CB1 receptors as a relevant therapy for FXS.

A.B.-G. was recipient of a predoctoral fellowship (Ministerio de Educación y Ciencia). S.M. is recipient of a Ramón y Cajal contract (Ministerio de Educación y Ciencia). This study was supported by grants from FRAXA Research Foundation (A.O. and S.M.), Grants from the Ministerio de Ciencia e Innovación (#BFU2015-68568-P to A.O., #SAF2014-59648-P to R.M. and SAF2013-45084-R to C.M., MINECO/FEDER, UE); Instituto de Salud Carlos III (RD06/0001/0001 to R.M. and CIBERNED PRY-15-404 to C.M.); Generalitat de Catalunya (SGR-2014-1547 to R.M.); ICREA (Institució Catalana de Recerca i Estudis Avançats) Academia to R.M.