Biology subjects

Galera-Lopez, L.

Publications and source records attributed to Galera-Lopez, L..

5 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↗

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↗

bioRxiv2021

Peripheral CB1 receptor blockade acts as a memory enhancer through an adrenergic-dependent mechanism

Peripheral inputs to the brain continuously shape its function and can influence the formation of non-emotional memory, but the underlying mechanisms have not been fully understood. Cannabinoid type-1 receptors (CB1R), widely distributed in the organism, is a well-recognized player in memory performance, and its systemic modulation significantly influences memory function. By assessing non-emotional memory in mice, we have now found a relevant role of peripheral CB1R in the formation of persistent memory. Indeed, peripherally restricted CB1R antagonism by using AM6545 showed a mnemonic effect that was occluded in adrenalectomized mice, after peripheral adrenergic blockade, or when vagus nerve was chemogenetically inhibited. Genetic CB1R deletion in dopamine {beta}-hydroxylase-expressing cells enhanced the formation of persistent memory, supporting a role of peripheral CB1R modulating the adrenergic tone. Notably, brain connectivity was affected by peripheral CB1R inhibition, and locus coeruleus activity and extracellular hippocampal norepinephrine, were increased. In agreement, intra-hippocampal {beta}-adrenergic blockade prevented AM6545 mnemonic effects. Together, we disclose a novel peripheral mechanism relevant for the modulation of the formation of persistent non-emotional memory.

neuroscience↗

bioRxiv2021

A low repeated dose of Δ9-tetrahydrocannabinol affects memory performance through serotonergic signalling in mice

Cannabis is the most widely used illicit drug worldwide. Its principal psychoactive component, {Delta}9-tetrahydrocannabinol (THC), acts as a partial agonist of the main cannabinoid receptor in the brain, the cannabinoid type-1 receptor (CB1R), that is responsible for the central effects of THC including memory impairment. CB1Rs may form heterodimers with the serotonin 5-HT2A receptor (5-HT2AR) which were found responsible for the memory impairment produced by acute high dose of THC in mice. In this study we investigated whether a repeated low dose of THC (1 mg/kg), with no acute consequence on memory performance, could eventually have deleterious cognitive effects. We found that this dose of THC impaired novel object-recognition memory and fear conditioning memory 24 h after the last of 7 consecutive daily treatments. At that time, a general enhancement of c-Fos expression was also observed in several brain regions of THC-exposed animals, as well as a decreased dendritic spine density on hippocampal CA1 pyramidal neurons that was accompanied by reduced long-term potentiation (LTP) at Schaffer collateral-CA1 synapses. Interestingly, an up-regulation in the expression of CB1R/5-HT2AR heterodimers was observed in the hippocampus after THC exposure and pre-treatment with the 5-HT2AR antagonist MDL 100,907 (0.01 mg/kg) prevented the enhanced heterodimerization and the THC-associated memory impairment. Together, these results reveal the significance of serotonergic signalling through 5-HT2ARs in the memory-impairing effects of repeated low doses of THC.

neuroscience↗

bioRxiv2020

Coexistence of amyloid-β and Tau hyperphosphorylation rescues cognitive and electrophysiological deficiencies in a mouse model of Alzheimer's disease

Alzheimers disease comprises amyloid-{beta} (A{beta}) and hyperphosphorylated Tau (P-Tau) accumulation, imbalanced neuronal activity, aberrant oscillatory rhythms, and cognitive deficits. Non-Demented with Alzheimers disease Neuropathology (NDAN) defines a novel clinical entity with A{beta} and Tau pathologies, but preserved cognition. The mechanisms underlying such neuroprotection remain undetermined and animal models are currently unavailable for NDAN. We show that J20/VLW mice, accumulating A{beta} and P-Tau, exhibit preserved hippocampal rhythmic activity and cognition, altered in J20 and VLW animals. Furthermore, we show that coexistence with A{beta} renders a particular P-Tau signature in hippocampal interneurons. The GABAergic septohippocampal pathway, responsible for hippocampal rhythmic activity, is preserved in J20/VLW mice, in contrast to single mutants. Our data highlight J20/VLW mice as a suitable animal model to understand the mechanisms driving cognitive preservation in NDAN and suggest that a differential P-Tau pattern in hippocampal interneurons prevents GABAergic septohippocampal innervation loss and alterations in local field potentials, avoiding cognitive deficits.

neuroscience↗