Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Alterations of this system contribute to the pathogenesis of several neurological and neurodevelopmental disorders. However, the involvement of the endocannabinoid system in the pathogenesis of Down syndrome has not been explored before. We used the best-characterized preclinical model of Down syndrome, the segmentally trisomic Ts65Dn model. In male Ts65Dn mice, cannabinoid type-1 receptor (CB1R) expression was enhanced and its function increased in hippocampal excitatory terminals. Knockdown of CB1R in the hippocampus of male Ts65Dn mice restored hippocampal-dependent memory. Concomitant with this result, pharmacological inhibition of CB1R restored memory deficits, hippocampal synaptic plasticity and adult neurogenesis in the subgranular zone of the dentate gyrus. Notably, the blockade of CB1R also normalized hippocampal-dependent memory in female Ts65Dn mice. To further investigate the mechanisms involved, we used a second transgenic mouse model overexpressing a single gene candidate for Down syndrome cognitive phenotypes, the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). CB1R pharmacological blockade similarly improved cognitive performance, synaptic plasticity and neurogenesis in transgenic male Dyrk1A mice. Our results identify CB1R as a novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.

A.N.-R. is the recipient of a predoctoral fellowship (Ministerio de Educación y Cultura, Spain). A.V.-O. is the recipient of a predoctoral fellowship from Jérôme Lejeune Foundation, France (Spanish Delegation). M.G.-G. was partially supported by FRAXA Research Foundation, United States. A.B-G. was the recipient of a predoctoral fellowship (Ministerio de Educación y Cultura). This study was supported by Jérôme Lejeune Foundation (French Delegation) to A.O.; Instituto de Salud Carlos III, Spain (#RD16/0017/0020) to R.M.; Ministerio de Economía, Innovación y Competitividad (MINECO), Spain (#BFU2015-68568-P to A.O., #SAF2014-59648-P and #SAF2017- 84060-R to R.M.; SAF2016-79956-R to M.D.); Catalan Foundation ‘La Marató de TV3’, Spain (#2016/20-30) to E.M.-G.; Junta de Andalucía, Spain (CVI-7290 to A.R.-M.); Generalitat de Catalunya, Spain (2014SGR-1547 and 2017SGR-669 to R.M.; 2014SGR-1125 to M.D.) and ICREA (Institució Catalana de Recerca i Estudis Avançats, Spain) Academia to A.O. and R.M. Grant “Unidad de Excelencia María de Maeztu”, funded by the MINECO (#MDM-2014-0370); PLAN E, Spain (Plan Español para el Estímulo de la Economía y el Empleo); FEDER, European Commission funding is also acknowledged