Biology subjects

Martinez-Torres, S.

Publications and source records attributed to Martinez-Torres, S..

6 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↗

bioRxiv2022

Nociception-dependent CCL21 induce dorsal root ganglia axonal growth via CCR7-ERK activation

While chemokines were originally described for their ability to induce cell migration, many studies show how chemokines also take part in a variety of other cell functions, acting as adaptable messengers in the communication between a diversity of cell types. In the nervous system, chemokines participate both in physiological and pathological processes, and while their expression is often described on glial and immune cells, growing evidence describe the expression of chemokines and their receptors in neurons, highlighting, their potential in auto- and paracrine signalling. In this study we analysed the role of nociception in the neuronal chemokinome, and their role in axonal growth. We found that stimulating TRPV1+ nociceptors induces a transient increase in CCL21. Interestingly we found that, this CCL21 increases neurite growth of large diameter proprioceptors in vitro. Consistent with this, we show that proprioceptors express the CCL21 receptor CCR7, and a CCR7 neutralizing antibody dose-dependently attenuates CCL21-induced neurite outgrowth. Mechanistically, we found that CCL21 binds locally to its receptor CCR7 at the growth cone, activating the downstream MEK-ERK pathway, that in turn activates N-WASP, triggering actin filament ramification in the growth cone, resulting in increased axonal growth.

cell biology↗

bioRxiv2022

Genetic control of neuronal activity enhances axonal growth only on permissive substrates

Neural tissue has limited regenerative ability, to cope with that, in the recent years a diverse set of novel tools have been used to tailor neurostimulation therapies and promote functional regeneration after axonal injuries. In this report, we explore cell-specific methods to modulate neuronal activity, including opto- and chemogenetics to assess the effect of specific neuronal stimulation in the promotion of axonal regeneration after injury. We found that opto- or chemogenetic modulations of neuronal activity on both dorsal root ganglia and corticospinal motor neurons increase their axonal growth capacity only on permissive substrates.

neuroscience↗

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↗