Neurocentre Magendie

Arnau BUSQUETS-GARCIA




Post-Doctorant

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17 publication(s) depuis Septembre 2009:


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01/04/2017 | Biol Psychiatry   IF 8.9
CB1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal.
Saravia R, Flores A, Plaza-Zabala A, Busquets-Garcia A, Pastor A, de la Torre R, Di Marzo V, Marsicano G, Ozaita A, Maldonado R, Berrendero F

Abstract:
BACKGROUND: Tobacco withdrawal is associated with deficits in cognitive function, including attention, working memory, and episodic memory. Understanding the neurobiological mechanisms involved in these effects is crucial because cognitive deficits during nicotine withdrawal may predict relapse in humans. METHODS: We investigated in mice the role of CB1 cannabinoid receptors (CB1Rs) in memory impairment and spine density changes induced by nicotine withdrawal precipitated by the nicotinic antagonist mecamylamine. Drugs acting on the endocannabinoid system and genetically modified mice were used. RESULTS: Memory impairment during nicotine withdrawal was blocked by the CB1R antagonist rimonabant or the genetic deletion of CB1R in forebrain gamma-aminobutyric acidergic (GABAergic) neurons (GABA-CB1R). An increase of 2-arachidonoylglycerol (2-AG), but not anandamide, was observed during nicotine withdrawal. The selective inhibitor of 2-AG biosynthesis O7460 abolished cognitive deficits of nicotine abstinence, whereas the inhibitor of 2-AG enzymatic degradation JZL184 did not produce any effect in cognitive impairment. Moreover, memory impairment was prevented by the selective mammalian target of rapamycin inhibitor temsirolimus and the protein synthesis inhibitor anisomycin. Mature dendritic spines on CA1 pyramidal hippocampal neurons decreased 4 days after the precipitation of nicotine withdrawal, when the cognitive deficits were still present. Indeed, a correlation between memory performance and mature spine density was found. Interestingly, these structural plasticity alterations were normalized in GABA-CB1R conditional knockout mice and after subchronic treatment with rimonabant. CONCLUSIONS: These findings underline the interest of CB1R as a target to improve cognitive performance during early nicotine withdrawal. Cognitive deficits in early abstinence are associated with increased relapse risk.




21/02/2017 | Mol Psychiatry   IF 15
Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice.
Busquets-Garcia A, Soria-Gomez E, Redon B, Mackenbach Y, Vallee M, Chaouloff F, Varilh M, Ferreira G, Piazza PV, Marsicano G

Abstract:
Cannabis-induced acute psychotic-like states (CIAPS) represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood. The use of antipsychotics and benzodiazepines against CIAPS is limited by side effects and/or by their ability to tackle only certain aspects of psychosis. Thus, safer wide-spectrum treatments are currently needed. Although the blockade of cannabinoid type-1 receptor (CB1) had been suggested as a therapeutical means against CIAPS, the use of orthosteric CB1 receptor full antagonists is strongly limited by undesired side effects and low efficacy. The neurosteroid pregnenolone has been recently shown to act as a potent endogenous allosteric signal-specific inhibitor of CB1 receptors. Thus, we tested in mice the potential therapeutic use of pregnenolone against acute psychotic-like effects of Delta9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis. We found that pregnenolone blocks a wide spectrum of THC-induced endophenotypes typically associated with psychotic-like states, including impairments in cognitive functions, somatosensory gating and social interaction. In order to capture THC-induced positive psychotic-like symptoms (e.g. perceptual delusions), we adapted a behavioral paradigm based on associations between different sensory modalities and selective devaluation, allowing the measurement of mental sensory representations in mice. Acting at hippocampal CB1 receptors, THC impaired the correct processing of mental sensory representations (reality testing) in an antipsychotic- and pregnenolone-sensitive manner. Overall, this work reveals that signal-specific inhibitors mimicking pregnenolone effects can be considered as promising new therapeutic tools to treat CIAPS.Molecular Psychiatry advance online publication, 21 February 2017; doi:10.1038/mp.2017.4.




09/11/2016 | Nature   IF 40.1
A cannabinoid link between mitochondria and memory.
Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, Busquets-Garcia A, Zottola AC, Delamarre A, Cannich A, Vincent P, Varilh M, Robin LM, Terral G, Garcia-Fernandez MD, Colavita M, Mazier W, Drago F, Puente N, Reguero L, Elezgarai I, Dupuy JW, Cota D, Lopez-Rodriguez ML, Barreda-Gomez G, Massa F, Grandes P, Benard G, Marsicano G

Abstract:
Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB1 receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1 receptors signal through intra-mitochondrial Galphai protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.




31/08/2016 | genes (basel)
Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model.
Gomis-Gonzalez M, Busquets-Garcia A, Matute C, Maldonado R, Mato S, Ozaita A

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.




19/08/2016 | oncotarget   IF 5.2
Glutamatergic stimulation induces GluN2B translation by the nitric oxide-Heme-Regulated eIF2alpha kinase in cortical neurons.
Ramos-Fernandez E, Tajes M, Ill-Raga G, Vargas L, Busquets-Garcia A, Bosch-Morato M, Guivernau B, Valls-Comamala V, Gomis M, Grau C, Fandos C, Rosen MD, Rabinowitz MH, Inestrosa N, Maldonado R, Altafaj X, Ozaita A, Alvarez A, Vicente R, Valverde MA, Munoz FJ

Abstract:
The activation of N-Methyl D-Aspartate Receptor (NMDAR) by glutamate is crucial in the nervous system function, particularly in memory and learning. NMDAR is composed by two GluN1 and two GluN2 subunits. GluN2B has been reported to participate in the prevalent NMDAR subtype at synapses, the GluN1/2A/2B. Here we studied the regulation of GluN2B expression in cortical neurons finding that glutamate up-regulates GluN2B translation through the action of nitric oxide (NO), which induces the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2alpha). It is a process mediated by the NO-heme-regulated eIF2alpha kinase (HRI), as the effect was avoided when a specific HRI inhibitor or a HRI small interfering RNA (siHRI) were used. We found that the expressed GluN2B co-localizes with PSD-95 at the postsynaptic ending, which strengthen the physiological relevance of the proposed mechanism. Moreover the receptors bearing GluN2B subunits upon NO stimulation are functional as high Ca2+ entry was measured and increases the co-localization between GluN2B and GluN1 subunits. In addition, the injection of the specific HRI inhibitor in mice produces a decrease in memory retrieval as tested by the Novel Object Recognition performance. Summarizing our data suggests that glutamatergic stimulation induces HRI activation by NO to trigger GluN2B expression and this process would be relevant to maintain postsynaptic activity in cortical neurons.




15/08/2016 | Proc Natl Acad Sci U S A   IF 9.6
Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation.
Busquets-Garcia A, Gomis-Gonzalez M, Srivastava RK, Cutando L, Ortega-Alvaro A, Ruehle S, Remmers F, Bindila L, Bellocchio L, Marsicano G, Lutz B, Maldonado R, Ozaita A

Abstract:
Stressful events can generate emotional memories linked to the traumatic incident, but they also can impair the formation of nonemotional memories. Although the impact of stress on emotional memories is well studied, much less is known about the influence of the emotional state on the formation of nonemotional memories. We used the novel object-recognition task as a model of nonemotional memory in mice to investigate the underlying mechanism of the deleterious effect of stress on memory consolidation. Systemic, hippocampal, and peripheral blockade of cannabinoid type-1 (CB1) receptors abolished the stress-induced memory impairment. Genetic deletion and rescue of CB1 receptors in specific cell types revealed that the CB1 receptor population specifically in dopamine beta-hydroxylase (DBH)-expressing cells is both necessary and sufficient for stress-induced impairment of memory consolidation, but CB1 receptors present in other neuronal populations are not involved. Strikingly, pharmacological manipulations in mice expressing CB1 receptors exclusively in DBH+ cells revealed that both hippocampal and peripheral receptors mediate the impact of stress on memory consolidation. Thus, CB1 receptors on adrenergic and noradrenergic cells provide previously unrecognized cross-talk between central and peripheral mechanisms in the stress-dependent regulation of nonemotional memory consolidation, suggesting new potential avenues for the treatment of cognitive aspects on stress-related disorders.




23/09/2015 | Neuron   IF 14
Habenular CB Receptors Control the Expression of Aversive Memories.
Soria-Gomez E, Busquets-Garcia A, Hu F, Mehidi A, Cannich A, Roux L, Louit I, Alonso L, Wiesner T, Georges F, Verrier D, Vincent P, Ferreira G, Luo M, Marsicano G

Abstract:
Expression of aversive memories is key for survival, but the underlying brain mechanisms are not fully understood. Medial habenular (MHb) axons corelease glutamate and acetylcholine onto target postsynaptic interpeduncular (IPN) neurons, but their role in aversive memories has not been addressed so far. We found that cannabinoid type 1 receptors (CB1R), key regulators of aversive responses, are present at presynaptic terminals of MHb neurons in the IPN. Conditional deletion of CB1R from MHb neurons reduces fear-conditioned freezing and abolishes conditioned odor aversion in mice, without affecting neutral or appetitively motivated memories. Interestingly, local inhibition of nicotinic, but not glutamatergic receptors in the target region IPN before retrieval, rescues these phenotypes. Finally, optogenetic electrophysiological recordings of MHb-to-IPN circuitry revealed that blockade of CB1R specifically enhances cholinergic, but not glutamatergic, neurotransmission. Thus, presynaptic CB1R control expression of aversive memories by selectively modulating cholinergic transmission at MHb synapses in the IPN.




11/08/2015 | bioessays   IF 4.4
Dissecting the cannabinergic control of behavior: The where matters.
Busquets-Garcia A, Desprez T, Metna-Laurent M, Bellocchio L, Marsicano G, Soria-Gomez E

Abstract:
The endocannabinoid system is the target of the main psychoactive component of the plant Cannabis sativa, the Delta9 -tetrahydrocannabinol (THC). This system is composed by the cannabinoid receptors, the endogenous ligands, and the enzymes involved in their metabolic processes, which works both centrally and peripherally to regulate a plethora of physiological functions. This review aims at explaining how the site-specific actions of the endocannabinoid system impact on memory and feeding behavior through the cannabinoid receptors 1 (CB1 R). Centrally, CB1 R is widely distributed in many brain regions, different cell types (e.g. neuronal or glial cells) and intracellular compartments (e.g. mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB1 R according to their cell-type localization (e.g. glutamatergic or GABAergic neurons). Thus, understanding the cellular and subcellular function of CB1 R will provide new insights and aid the design of new compounds in cannabinoid-based medicine. Also watch the Video Abstract.




23/02/2015 | Antioxid Redox Signal   IF 7.6
Physiological Control of Nitric Oxide on neuronal BACE1 Translation by Heme-Regulated Eif2-alpha Kinase HRI Induces Synaptogenesis.
Ill-Raga G, Tajes M, Busquets-Garcia A, Ramos-Fernandez E, Vargas LM, Bosch-Morato M, Guivernau B, Valls-Comamala V, Eraso-Pichot A, Guix FX, Fandos C, Rosen MD, Rabinowitz MH, Maldonado R, Alvarez AR, Ozaita A, Munoz FJ

Abstract:
Aims: Hippocampus is the brain center for memory formation, a process that requires synaptogenesis. However hippocampus is dramatically compromised in Alzheimer's disease due to the accumulation of amyloid alpha-peptide, whose production is initiated by BACE1. It is known that pathological stressors activate BACE1 translation through the phosphorylation of the eukaryotic initiation factor-2alpha (eIF2alpha) by GCN2, PERK or PKR kinases leading to amyloidogenesis. However BACE1 physiological regulation is still unclear. Since nitric oxide (NO) participates directly in hippocampal glutamatergic signaling we investigated the neuronal role of the eIF2alpha kinase HRI, which can bind NO by a heme group, in BACE1 translation and its physiological consequences. Results: We found that BACE1 is expressed upon glutamate activation being NO the downstream effector by triggering eIF2alpha phosphorylation, as it was obtained by western blot and luciferase assay. It is due to the activation of HRI by NO as assayed by western blot and immunofluorescence with a HRI inhibitor and HRI siRNA. BACE1 expression was early detected at synaptic spines contributing to spine growth and consolidating the hippocampal memory as assayed with mice treated with HRI or neuronal NO synthase inhibitors. Innovation: We provide the first description that HRI and eIF2alpha are working in physiological conditions in brain under the control of nitric oxide and glutamate signaling, and also that BACE1 has a physiological role in hippocampal function. Conclusion: We conclude BACE1 translation is controlled by NO through HRI in glutamatergic hippocampal synapses where it plays physiological functions allowing the spine growth and memory consolidation.




14/05/2014 | Int J Biochem Cell Biol   IF 4.9
New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.
Busquets-Garcia A, Maldonado R, Ozaita A

Abstract:
Fragile X syndrome is the most common monogenetic form of intellectual disability and is a leading cause of autism. This syndrome is produced by the reduced transcription of the fragile X mental retardation (FMR1) gene, and it is characterized by a range of symptoms heterogeneously expressed in patients such as cognitive impairment, seizure susceptibility, altered pain sensitivity and anxiety. The recent advances in the understanding of the pathophysiological mechanisms involved have opened novel potential therapeutic approaches identified in preclinical rodent models as a necessary preliminary step for the subsequent evaluation in patients. Among those possible therapeutic approaches, the modulation of the metabotropic glutamate receptor signaling or the GABA receptor signaling have focused most of the attention. New findings in the animal models open other possible therapeutic approaches such as the mammalian target of rapamycin signaling pathway or the endocannabinoid system. This review summarizes the emerging data recently obtained in preclinical models of fragile X syndrome supporting these new therapeutic perspectives.