Biology subjects

de los Reyes-Ramirez, L.

Publications and source records attributed to de los Reyes-Ramirez, L..

4 recordsLinked to original sources

bioRxiv2025

CB1 receptor inhibition in fragile X syndrome mice impacts alternative splicing alterations in hippocampal synaptoneurosomal transcriptome

BackgroundFragile X syndrome (FXS) conveys the most frequent heritable genetic cause of intellectual disability and autism. It is caused by a CGG repeat expansion in FMR1 gene that leads to the loss of fragile X messenger ribonucleoprotein 1 (FMRP). FMRP is highly abundant in synapses, where regulates mRNAs to maintain synaptic plasticity. Treatments under development significantly ameliorate neurological and behavioral landmarks in the mouse model of the disorder, the Fmr1 knockout (FX) mouse. Specifically, previous studies revealed that pharmacological and genetic inhibition of cannabinoid type-1 receptor (CB1R) restored phenotypic traits in FX mice. However, the molecular hallmarks associated with this experimental therapeutic intervention are largely unknown. MethodsFirst, we aimed to evaluate the validity of synaptoneurosomes preparations to investigate specific mRNA modifications at synapses. Afterwards, combining in silico high-throughput analysis and biochemical determinations, we analyzed the hippocampal synaptoneurosomal transcriptome after pharmacological inhibition of CB1R with the specific antagonist/inverse agonist rimonabant in FX male mice ResultsWe verified that synaptoneurosomes provide an accurate representation of synaptic composition and function. Then, we found that rimonabant treatment had a limited impact at gene expression level but produced significant modifications in transcript expression. Indeed, detailed analysis of alternative splicing events revealed a relevant number of events in which splicing was reverted from the FX form to the WT form by the treatment. LimitationsWe demonstrated that rimonabant treatment alters the AS landscape in FX hippocampal synaptoneurosomes; however, further studies are needed to elucidate if other neural components also contribute to the modifications and whether the findings are specific to rimonabant treatment or to CB1R inhibition at synapses. In addition, additional research could be required to clarify whether the changes in AS events could be affected by interindividual variability or technical protocols. ConclusionsWe determined that the AS landscape is modified in FX hippocampal synaptoneurosomes and that these changes are sensitive to rimonabant treatment which could explain the beneficial effects of this experimental therapeutic approach in FXS. Altogether, our results reveal a new level of complexity in the effect of pharmacological treatment to improve symptoms in the context of FXS.

neuroscience↗

bioRxiv2025

A serotonergic mechanism is involved in the pro-cognitive effect of AM6545 treatment in a mouse model of fragile X syndrome

Fragile X syndrome (FXS) is the principal monogenic syndrome leading to inherited intellectual disability and autism. It is caused by the silencing of FMR1 gene that leads to the loss in the expression of its encoded protein, the fragile X messenger ribonucleoprotein 1 (FMRP). In synapses, FMRP has a key role in local mRNA modulation to maintain synaptic plasticity. The Fmr1 KO (FX) mouse model shows cognitive impairment and some of the synaptic traits present in individuals with FXS together with alterations in gut microbiota. Previous studies revealed that pharmacological and genetic cannabinoid type-1 receptor (CB1R) inhibition significantly prevented central key alterations in FX mice. Here, we aimed to evaluate the effect of a sub-chronic treatment with the largely peripherally-restricted CB1R antagonist AM6545. We found that AM6545 reduced memory deficits and restored enhanced hippocampal mGluR5-dependent long-term depression and aberrant dendritic spine density in FX mice. At the peripheral level, AM6545 modified altered FX mice fecal microbiota composition, while in the hippocampus AM6545 treatment upregulated hippocampal Htr4, the gene encoding for serotonin receptor 4 (5-HT4R) This upregulation positively correlated with memory performance. Notably, acute pharmacological blockade of 5-HT4R abolished the pro-cognitive effect produced by AM6545. Together, our results suggest that peripheral CB1R inhibition ameliorates key alterations in FX mouse model and modifies the expression of serotonergic receptors important for cognitive performance.

animal behavior and cognition↗

bioRxiv2023

Sub-chronic peripheral CB1R inhibition enhances cognitive performance and induces hippocampal synaptic plasticity changes in naive mice

Background and PurposeThe peripheral contribution to brain function and cognitive performance is far from understood. Cannabinoid type-1 receptor (CB1R) is classically pictured in the central nervous system to have such a role. We previously demonstrated a novel mechanism where the acute peripheral CB1R inhibition in mice prolongs memory persistence. Here, we take advance of the repeated exposure to the peripherally-restricted CB1R antagonist to further reveal cognitive improvements and the hippocampal mechanisms involved. Experimental ApproachWe evaluated in young adult male and female mice the behavioural consequences of a sub-chronic treatment with AM6545. Moreover, an unbiased transcriptomic analysis, as well as electrophysiological and biochemical studies, were performed in the hippocampus of treated mice to elucidate the central cellular and molecular consequences of such peripheral approach. Key ResultsSub-chronic inhibition of peripheral CB1R with AM6545 resulted in enhanced memory in low and high arousal conditions. Moreover, executive function was facilitated after repeated AM6545 administration, further strengthening the cognitive improving properties of peripheral CB1R inhibition. Transcriptional analysis of hippocampal synaptoneurosomes from treated male and female mice revealed a sex-dependent modulation of synaptic transcripts by AM6545. Notably, AM6545 occluded long-term potentiation in CA3-CA1 synapses while enhancing input-output relation. This was accompanied by an increase in the hippocampal expression of Bdnf and Ngf. Conclusion and ImplicationsOur results show that peripheral CB1R inhibition contributes to the modulation of memory persistence, executive function, and hippocampal synaptic plasticity in mice, further indicating that peripheral CB1R could act as a target for a novel class of nootropic compounds. What is already known?- Acute peripheral CB1R inhibition enhances object-recognition memory persistence in mice. - Such enhancement occurs through a noradrenergic mechanism involving the vagus nerve. What does this study add?- Peripheral CB1R inhibition modifies synaptoneurosomal transcriptome in the hippocampus of mice. - No tolerance and no side effects were observed after peripheral CB1R inhibition. What is the clinical significance?- Peripheral CB1R inhibition may function as a novel strategy for cognitive improvement.

neuroscience↗

bioRxiv2021

Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild to moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no available treatments to ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with sub-chronic (10 d) JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiac function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.

animal behavior and cognition↗