Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome

Abstract

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 tyrosinephosphorylation-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.

Prefrontal–hippocampal functional connectivity encodes recognition memory and is impaired in intellectual disability

“…Consistent with the literature (1,34,37), WT mice explored more novel objects than familiar objects in the 24 h memory test, and thus, discrimination indexes (DIs) for the novel object were positive ( Fig. 3 D, Left).…”

“…DS individuals show deficits in declarative memory that could arise from deficient memory consolidation and also from poor memory acquisition, retrieval, and learning abilities (54). In Ts65Dn mice declarative memory is also faulty, as revealed by poor spatial navigation and recognition memory (1,5,34,35,37). Here the DIs of TS mice were smaller than those of WT mice because individual explorations were shorter, despite TS mice tending to visit the objects on more occasions, possibly reflecting hyperlocomotion and attentional deficits (26,54,55).…”

A Guide to Targeting the Endocannabinoid System in Drug Design

“…The same compound (2.5-5 mg/kg) also improved cognitive deficits caused by scopolamine in the rodent model [147]. Rimonabant (1 mg/kg) improved memory in Down syndrome mice [148]. Pregnenolone (2-6 mg/kg), an endogenous CB1 NAM, reduced memory impairment caused by ∆9-THC administration in rodent models [149].…”

Cannabinoids

“…Results from an investigation in a mouse model of Down syndrome are very different. Here, interestingly, pharmacological blockade of CB 1 receptor led to the alleviation of impaired cognitive performance, synaptic plasticity, and neurogenesis, 125 an effect possibly explained by the pathology of enhanced hippocampal CB 1 receptor expression and concomitant increased receptor function at excitatory terminals.…”