Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model

Abstract

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 Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects.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.

Activation of Serotonin 5-HT7 Receptors Modulates Hippocampal Synaptic Plasticity by Stimulation of Adenylate Cyclases and Rescues Learning and Behavior in a Mouse Model of Fragile X Syndrome

“…We used the NOR test to study cortex- and hippocampus-dependent novelty detection ability (Broadbent et al, 2010 ), which is known to involve hippocampal mGluR-LTD (reviewed by Sanderson et al, 2016 ). We first confirmed that recognition memory tested by NOR is impaired in Fmr1 KO mice (Ventura et al, 2004 ; King and Jope, 2013 ; Franklin et al, 2014 ; Gomis-González et al, 2016 ), since discrimination index is impaired compared to WT littermates and less time is spent exploring the novel object. Interestingly, Fmr1 KO mice showed a preference for the familiar compared to the novel object, consistent with previous studies demonstrating alterations of novelty preferences, with stereotyped behavior and restricted interests, in autism spectrum disorders (Jacob et al, 2009 ).…”

“…Fmr1 KO mice show a cognitive impairment when evaluated by Novel object recognition (NOR) tasks based on the natural tendency of rodents to explore unfamiliar objects (Ventura et al, 2004 ; King and Jope, 2013 ; Franklin et al, 2014 ; Gomis-González et al, 2016 ). Here we first confirmed that Fmr1 KO presented a damage of recognition memory, since their D index did not significantly differ from zero ( t (11) = 1.864, P = 0.089, n = 12; Figures 6A,B ).…”

The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models

“…Interestingly, treatment with the CB2 receptor antagonist AM630 only affected anxiety-like behavior and audiogenic seizure susceptibility, suggesting a distinct involvement of CB1 and CB2 receptors in the behavioral manifestations of FXS [ 42 ]. The beneficial effect of CB1 receptor blockade in the cognitive performance of Fmr1 knockout mice was confirmed in a recent study by Gomis-Gonzales et al [ 43 ]. These authors showed that both low doses of rimonabant and a low dose of the CB1 receptor neutral antagonist NESS0327 prevented cognitive deficits in the Fmr1 knockout mice as measured in the novel object recognition test.…”

Auricular transcutaneous vagus nerve stimulation improves memory persistence in naïve mice and in an intellectual disability mouse model

“…We then tested the potential of our atVNS protocol in a well-characterized mouse model of fragile X syndrome, the Fmr1KO model [7], which shows a poor object-recognition memory performance 24 h after familiarization. This marked phenotype of Fmr1KO mice, which can be improved through pharmacological interventions [24,25], was also normalized through atVNS. Discrimination index of WT littermates was not affected after atVNS, since the novel object-recognition test presents a ceiling effect.…”