Page personnelle


Principal Investigator

Phone : 33(0)5 57 57 37 56 / 33(0)5 57 57 37 61
Send an email

PhD à l'Institut Max-Planck de Munich (1997-2001)
Post-Doc, Institut Max-Planck, Munich (2001-2004)
CR1 Neurocentre Magendie, Bordeaux (2007)

160 publication(s) since Mai 1996:

Sort by

* equal contribution
The indicated IF have been collected by the Web of Sciences in

18/08/2020 | Cell Rep   IF 8.1
Specific Hippocampal Interneurons Shape Consolidation of Recognition Memory.
Oliveira da Cruz JF, Busquets-Garcia A, Zhao Z, Varilh M, Lavanco G, Bellocchio L, Robin L, Cannich A, Julio-Kalajzic F, Leste-Lasserre T, Maitre M, Drago F, Marsicano G, Soria-Gomez E

A complex array of inhibitory interneurons tightly controls hippocampal activity, but how such diversity specifically affects memory processes is not well understood. We find that a small subclass of type 1 cannabinoid receptor (CB1R)-expressing hippocampal interneurons determines episodic-like memory consolidation by linking dopamine D1 receptor (D1R) signaling to GABAergic transmission. Mice lacking CB1Rs in D1-positive cells (D1-CB1-KO) display impairment in long-term, but not short-term, novel object recognition memory (NOR). Re-expression of CB1Rs in hippocampal D1R-positive cells rescues this NOR deficit. Learning induces an enhancement of in vivo hippocampal long-term potentiation (LTP), which is absent in mutant mice. CB1R-mediated NOR and the associated LTP facilitation involve local control of GABAergic inhibition in a D1-dependent manner. This study reveals that hippocampal CB1R-/D1R-expressing interneurons control NOR memory, identifying a mechanism linking the diversity of hippocampal interneurons to specific behavioral outcomes.

10/08/2020 | eLife   IF 7.1
Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination.
Blazquez C, Ruiz-Calvo A, Bajo-Graneras R, Baufreton JM, Resel E, Varilh M, Pagano Zottola AC, Mariani Y, Cannich A, Rodriguez-Navarro JA, Marsicano G, Galve-Roperh I, Bellocchio L, Guzman M

The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo. Boosting autophagy, either pharmacologically (with temsirolimus) or by dietary intervention (with trehalose), rescued the Delta(9)-tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagy-modulating strategies in vivo showed that cannabinoid CB1 receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of Delta(9)-tetrahydrocannabinol by inhibiting local autophagy. Taken together, these findings identify inhibition of autophagy as an unprecedented mechanistic link between cannabinoids and motor performance, and suggest that activators of autophagy might be considered as potential therapeutic tools to treat specific cannabinoid-evoked behavioral alterations.

03/08/2020 |
Sex-dependent pharmacological profiles of the synthetic cannabinoid MMB-Fubinaca.
Oliveira da Cruz JF, Ioannidou C, Pagano Zottola AC, Muguruza C, Gomez-Sotres P, Fernandez M, Callado LF, Marsicano G, Busquets-Garcia A

Synthetic cannabinoids have emerged as novel psychoactive substances with damaging consequences for public health. They exhibit high affinity at the cannabinoid type-1 (CB1 ) receptor and produce similar and often more potent effects as other CB1 receptor agonists. However, we are still far from a complete pharmacological understanding of these compounds. In this study, by using behavioral, molecular, pharmacological, and electrophysiological approaches, we aimed at characterizing several in vitro and in vivo pharmacological effects of the synthetic cannabinoid MMB-Fubinaca (also known as AMB-Fubinaca or FUB-AMB), a particular synthetic cannabinoid. MMB-Fubinaca stimulates CB1 receptor-mediated functional coupling to G-proteins in mouse and human brain preparations in a similar manner as the CB1 receptor agonist WIN55,512-2 but with a much greater potency. Both drugs similarly activate the CB1 receptor-dependent extracellular signal-regulated kinase (ERK) pathway. Notably, in vivo administration of MMB-Fubinaca in mice induced greater behavioral and electrophysiological effects in male than in female mice in a CB1 receptor-dependent manner. Overall, these data provide a solid pharmacological profiling of the effects of MMB-Fubinaca and important information about the mechanisms of action underlying its harmful impact in humans. At the same time, they reinforce the significant sexual dimorphism of cannabinoid actions, which will have to be taken into account in future animal and clinical studies.

08/07/2020 | Nature   IF 42.8
Glucose metabolism links astroglial mitochondria to cannabinoid effects.
Jimenez-Blasco D, Busquets-Garcia A, Hebert-Chatelain E, Serrat R, Vicente-Gutierrez C, Ioannidou C, G, Marsicano G

Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses(1-5). By contrast, astrocytes are under neuronal control through specific neurotransmitter receptors(5-7). However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses is unclear. Here we show that activation of mouse astroglial type-1 cannabinoid receptors associated with mitochondrial membranes (mtCB(1)) hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioural responses in social interaction assays. Specifically, activation of astroglial mtCB(1) receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4, which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the hypoxia-inducible factor 1 pathway, eventually resulting in neuronal redox stress and impairment of behavioural responses in social interaction assays. Genetic and pharmacological correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behaviour. These findings suggest that mtCB(1) receptor signalling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behaviour in mice.

18/05/2020 | Nat Commun   IF 12.1
Author Correction: Structural basis of astrocytic Ca(2+) signals at tripartite synapses.
Arizono M, Inavalli VVGK, Panatier A, Pfeiffer T, Angibaud J, Levet F, Veer MJTT, Stobart J, Bellocchio L, Mikoshiba K, Marsicano G, Weber B, Oliet SHR, Nagerl UV

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

20/04/2020 | Nat Commun   IF 12.1
Structural basis of astrocytic Ca(2+) signals at tripartite synapses.
Arizono M, Inavalli VVGK, Panatier A, Pfeiffer T, Angibaud J, Levet F, Ter Veer MJT, Stobart J, Bellocchio L, Mikoshiba K, Marsicano G, Weber B, Oliet SHR, Nagerl UV

Astrocytic Ca(2+) signals can be fast and local, supporting the idea that astrocytes have the ability to regulate single synapses. However, the anatomical basis of such specific signaling remains unclear, owing to difficulties in resolving the spongiform domain of astrocytes where most tripartite synapses are located. Using 3D-STED microscopy in living organotypic brain slices, we imaged the spongiform domain of astrocytes and observed a reticular meshwork of nodes and shafts that often formed loop-like structures. These anatomical features were also observed in acute hippocampal slices and in barrel cortex in vivo. The majority of dendritic spines were contacted by nodes and their sizes were correlated. FRAP experiments and Ca(2+) imaging showed that nodes were biochemical compartments and Ca(2+) microdomains. Mapping astrocytic Ca(2+) signals onto STED images of nodes and dendritic spines showed they were associated with individual synapses. Here, we report on the nanoscale organization of astrocytes, identifying nodes as a functional astrocytic component of tripartite synapses that may enable synapse-specific communication between neurons and astrocytes.

07/01/2020 | Neuron   IF 14.4
Dopamine-Evoked Synaptic Regulation in the Nucleus Accumbens Requires Astrocyte Activity.
Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, Quintana R, Rothwell PE, Lujan R, Marsicano G, Martin ED, Thomas MJ, Kofuji P, Araque A

Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson's disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca(2+) elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca(2+), stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.

09/12/2019 | J Neurosci Methods   IF 2.8
Alpha technology: A powerful tool to detect mouse brain intracellular signaling events.
Zanese M*, Tomaselli G*, Roullot-Lacarriere V, Moreau M, Bellocchio L, Grel A, Marsicano G, Sans N, Vallee M, Revest JM

BACKGROUND: Phosphorylation by protein kinases is a fundamental molecular process involved in the regulation of signaling activities in living organisms. Understanding this complex network of phosphorylation, especially phosphoproteins, is a necessary step for grasping the basis of cellular pathophysiology. Studying brain intracellular signaling is a particularly complex task due to the heterogeneous complex nature of the brain tissue, which consists of many embedded structures. NEW METHOD: Overcoming this degree of complexity requires a technology with a high throughput and economical in the amount of biological material used, so that a large number of signaling pathways may be analyzed in a large number of samples. We have turned to Alpha (Amplified Luminescent Proximity Homogeneous Assay) technology. COMPARISON WITH EXISTING METHOD: Western blot is certainly the most commonly used method to measure the phosphorylation state of proteins. Even though Western blot is an accurate and reliable method for analyzing modifications of proteins, it is a time-consuming and large amounts of samples are required. Those two parameters are critical when the goal of the research is to comprehend multi-signaling proteic events so as to analyze several targets from small brain areas. RESULT: Here we demonstrate that Alpha technology is particularly suitable for studying brain signaling pathways by allowing rapid, sensitive, reproducible and semi-quantitative detection of phosphoproteins from individual mouse brain tissue homogenates and from cell fractionation and synaptosomal preparations of mouse hippocampus. CONCLUSION: Alpha technology represents a major experimental step forward in unraveling the brain phosphoprotein-related molecular mechanisms involved in brain-related disorders.

24/10/2019 | Psychoneuroendocrinology   IF 4
The ergogenic impact of the glucocorticoid prednisolone does not translate into increased running motivation in mice.
Redon B, Violleau C, Georges F, Marsicano G, Chaouloff F

Glucocorticoids, such as prednisolone, are considered sport doping agents owing to their ergogenic properties. These are accounted for by peripheral mechanisms associated with energetic and anti-inflammatory processes. However, because glucocorticoids target brain tissues, it is likely that these ergogenic impacts are associated with central effects. One of these might be reward motivation, which relies on glucocorticoid receptor-expressing mesocorticolimbic dopaminergic neurons. In keeping with this possibility, this study has explored in mice whether repeated prednisolone administration (5 or 15mug/ml of drinking water for 10 days) affected intrinsic motivation for running, a strong reinforcer in rodents. Running motivation was assessed by means of a cued-reward motivated instrumental task wherein wheel-running was conditioned by prior nose poke responses under fixed (FR), and then progressive (PR), ratio reinforcement schedules. Sub-chronic ingestion of prednisolone decreased the running distance covered during each rewarded sequence under FR schedules. This finding did not extend to wheel-running performances in mice provided free (i.e. unconditioned) wheel-running opportunities. Running motivation, as estimated under a PR reinforcement schedule, was found to be decreased (lowest concentration) or to remain unaffected (highest concentration) by prednisolone concentration. Lastly, an inter-individual analysis of the respective effects of prednisolone on muscular endurance (as assessed in the wire grid-hanging test) and on running motivation indicated that the former was not predictive of the latter. This observation suggests that prednisolone ergogenic impacts might occur without any concomitant increase in intrinsic exercise motivation.

11/08/2019 | j pers   IF 3.1
Stability and change of basic personal values in early adolescence: A 2-year longitudinal study.
Vecchione M, Schwartz SH, Davidov E, Cieciuch J, Alessandri G, Marsicano G

OBJECTIVE: We examined patterns of change and stability in the whole set of 10 Schwartz values over 2 years during early adolescence. METHOD: Participants completed the Portrait Values Questionnaire repeatedly throughout the junior high school years. The study involved six waves of data and a total of 382 respondents aged 10 years at the first measurement occasion (43% female). We investigated multiple types of stability in the values: mean-level, rank-order, and ipsative stability. RESULTS: At the mean-level, self-enhancement, and Openness to change values increased in importance. Self-direction and hedonism values showed the greatest increase-about one-third of a standard deviation. Conservation and self-transcendence values did not change with the exception of tradition, which decreased slightly. After correcting for measurement error, rank-order stability coefficients ranged from .39 (hedonism) to .77 (power). Correlations between value hierarchies measured 2 years apart were >/=.85 for 75% of respondents, and