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Luigi BELLOCCHIO




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32 publication(s) since Décembre 2006:


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23/03/2019 | Neuropharmacology   IF 4.4
Astroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons.
Ruiz-Calvo A, Bajo-Graneras R, Maroto IB, Zian D, Grabner GF, Garcia-Taboada E, Resel E, Zechner R, Zimmermann R, Ortega-Gutierrez S, Galve-Roperh I, Bellocchio L, Guzman M

Abstract:
Cannabinoids exert neuroprotection in a wide array of preclinical models. A number of these studies has focused on cannabinoid CB1 receptors in striatal medium spiny neurons (MSNs) and the most characteristic MSN-degenerative disease, Huntington's disease (HD). Accruing evidence supports that astrocytes contribute to drive HD progression, and that they express CB1 receptors, degrade endocannabinoids, and modulate endocannabinergic transmission. However, the possible role of the astroglial endocannabinoid system in controlling MSN integrity remains unknown. Here, we show that JZL-184, a selective inhibitor of monoacylglycerol lipase (MGL), the key enzyme that deactivates the endocannabinoid 2-arachidonoylglycerol, prevented the mutant huntingtin-induced up-regulation of the pro-inflammatory cytokine tumor necrosis factor-alpha in primary mouse striatal astrocytes via CB1 receptors. To study the role of astroglial MGL in vivo, we injected stereotactically into the mouse dorsal striatum viral vectors that encode mutant or normal huntingtin under the control of the glial fibrillary acidic protein promoter. We observed that, in wild-type mice, pharmacological blockade of MGL with JZL-184 (8mg/kg/day, i.p.) conferred neuroprotection against mutant huntingtin-induced striatal damage, as evidenced by the prevention of MSN loss, astrogliosis, and motor coordination impairment. We next found that conditional mutant mice bearing a genetic deletion of MGL selectively in astroglial cells (MGL(floxed/floxed;GFAP-Cre/+) mice) were resistant to mutant huntingtin-induced MSN loss, astrogliosis, and motor coordination impairment. Taken together, these data support that astroglial MGL controls the availability of a 2-arachidonoylglycerol pool that ensues protection of MSNs in the mouse striatum in vivo, thus providing a potential druggable target for reducing striatal neurodegeneration.




06/06/2018 | Neuron   IF 14.4
Astroglial CB1 Receptors Determine Synaptic D-Serine Availability to Enable Recognition Memory.
Robin LM*, Cruz J*, Oliveira da Cruz JF, Langlais VC, Martin-Fernandez M, Metna-Laurent M, Busquets-Garcia A, Bellocchio L, Soria-Gomez E, Papouin T, Varilh M, Sherwood MW, Belluomo I, Balcells G, Matias I, Bosier B, Drago F, Van Eeckhaut A, Smolders I, Georges F, Araque A, Panatier A, Oliet SHR*, Marsicano G*

Abstract:
Bidirectional communication between neurons and astrocytes shapes synaptic plasticity and behavior. D-serine is a necessary co-agonist of synaptic N-methyl-D-aspartate receptors (NMDARs), but the physiological factors regulating its impact on memory processes are scantly known. We show that astroglial CB1 receptors are key determinants of object recognition memory by determining the availability of D-serine at hippocampal synapses. Mutant mice lacking CB1 receptors from astroglial cells (GFAP-CB1-KO) displayed impaired object recognition memory and decreased in vivo and in vitro long-term potentiation (LTP) at CA3-CA1 hippocampal synapses. Activation of CB1 receptors increased intracellular astroglial Ca(2+) levels and extracellular levels of D-serine in hippocampal slices. Accordingly, GFAP-CB1-KO displayed lower occupancy of the co-agonist binding site of synaptic hippocampal NMDARs. Finally, elevation of D-serine levels fully rescued LTP and memory impairments of GFAP-CB1-KO mice. These data reveal a novel mechanism of in vivo astroglial control of memory and synaptic plasticity via the D-serine-dependent control of NMDARs.




26/02/2018 | Glia   IF 5.8
Localization of the cannabinoid type-1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus.
Gutierrez-Rodriguez A, Bonilla-Del Rio I, Puente N, Gomez-Urquijo SM, Fontaine CJ, Egana-Huguet J, Elezgarai I, Ruehle S, Lutz B, Robin LM, Soria-Gomez E, Bellocchio L, Padwal JD, van der Stelt M, Mendizabal-Zubiaga J, Reguero L, Ramos A, Gerrikagoitia I, Marsicano G, Grandes P

Abstract:
Astroglial type-1 cannabinoid (CB1 ) receptors are involved in synaptic transmission, plasticity and behavior by interfering with the so-called tripartite synapse formed by pre- and post-synaptic neuronal elements and surrounding astrocyte processes. However, little is known concerning the subcellular distribution of astroglial CB1 receptors. In particular, brain CB1 receptors are mostly localized at cells' plasmalemma, but recent evidence indicates their functional presence in mitochondrial membranes. Whether CB1 receptors are present in astroglial mitochondria has remained unknown. To investigate this issue, we included conditional knock-out mice lacking astroglial CB1 receptor expression specifically in glial fibrillary acidic protein (GFAP)-containing astrocytes (GFAP-CB1 -KO mice) and also generated genetic rescue mice to re-express CB1 receptors exclusively in astrocytes (GFAP-CB1 -RS). To better identify astroglial structures by immunoelectron microscopy, global CB1 knock-out (CB1 -KO) mice and wild-type (CB1 -WT) littermates were intra-hippocampally injected with an adeno-associated virus expressing humanized renilla green fluorescent protein (hrGFP) under the control of human GFAP promoter to generate GFAPhrGFP-CB1 -KO and -WT mice, respectively. Furthermore, double immunogold (for CB1 ) and immunoperoxidase (for GFAP or hrGFP) revealed that CB1 receptors are present in astroglial mitochondria from different hippocampal regions of CB1 -WT, GFAP-CB1 -RS and GFAPhrGFP-CB1 -WT mice. Only non-specific gold particles were detected in mouse hippocampi lacking CB1 receptors. Altogether, we demonstrated the existence of a precise molecular architecture of the CB1 receptor in astrocytes that will have to be taken into account in evaluating the functional activity of cannabinergic signaling at the tripartite synapse.




06/12/2017 | Neuron   IF 14.4
Endocannabinoid Actions on Cortical Terminals Orchestrate Local Modulation of Dopamine Release in the Nucleus Accumbens.
Mateo Y, Johnson KA, Covey DP, Atwood BK, Wang HL, Zhang S, Gildish I, Cachope R, Bellocchio L, Guzman M, Morales M, Cheer JF, Lovinger DM

Abstract:
Dopamine (DA) transmission mediates numerous aspects of behavior. Although DA release is strongly linked to firing of DA neurons, recent developments indicate the importance of presynaptic modulation at striatal dopaminergic terminals. The endocannabinoid (eCB) system regulates DA release and is a canonical gatekeeper of goal-directed behavior. Here we report that extracellular DA increases induced by selective optogenetic activation of cholinergic neurons in the nucleus accumbens (NAc) are inhibited by CB1 agonists and eCBs. This modulation requires CB1 receptors on cortical glutamatergic afferents. Dopamine increases driven by optogenetic activation of prefrontal cortex (PFC) terminals in the NAc are similarly modulated by activation of these CB1 receptors. We further demonstrate that this same population of CB1 receptors modulates optical self-stimulation sustained by activation of PFC afferents in the NAc. These results establish local eCB actions on PFC terminals within the NAc that inhibit mesolimbic DA release and constrain reward-driven behavior.




31/10/2017 | Cereb Cortex   IF 5.4
Pathway-Specific Control of Striatal Neuron Vulnerability by Corticostriatal Cannabinoid CB1 Receptors.
Ruiz-Calvo A, Maroto IB, Bajo-Graneras R, Chiarlone A, Gaudioso A, Ferrero JJ, Resel E, Sanchez-Prieto J, Rodriguez-Navarro JA, Marsicano G, Galve-Roperh I, Bellocchio L, Guzman M

Abstract:
The vast majority of neurons within the striatum are GABAergic medium spiny neurons (MSNs), which receive glutamatergic input from the cortex and thalamus, and form two major efferent pathways: the direct pathway, expressing dopamine D1 receptor (D1R-MSNs), and the indirect pathway, expressing dopamine D2 receptor (D2R-MSNs). While molecular mechanisms of MSN degeneration have been identified in animal models of striatal damage, the molecular factors that dictate a selective vulnerability of D1R-MSNs or D2R-MSNs remain unknown. Here, we combined genetic, chemogenetic, and pharmacological strategies with behavioral and neurochemical analyses, and show that the pool of cannabinoid CB1 receptor (CB1R) located on corticostriatal terminals efficiently safeguards D1R-MSNs, but not D2R-MSNs, from different insults. This cell-specific response relies on the regulation of glutamatergic signaling, and is independent from the CB1R-dependent control of astroglial activity in the striatum. These findings define cortical CB1R as a pivotal synaptic player in dictating a differential vulnerability of D1R-MSNs versus D2R-MSNs, and increase our understanding of the role of coordinated cannabinergic-glutamatergic signaling in establishing corticostriatal circuits and its dysregulation in neurodegenerative diseases.




09/11/2016 | Nature   IF 43.1
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.




12/10/2016 | J Neurosci   IF 6.1
Sustained Gq-Protein Signaling Disrupts Striatal Circuits via JNK.
Bellocchio L, Ruiz-Calvo A, Chiarlone A, Cabanas M, Resel E, Cazalets JR, Blazquez C, Cho YH, Galve-Roperh I, Guzman M

Abstract:
The dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. The functionality of striatal neurons is tightly controlled by various metabotropic receptors. Whereas the Gs/Gi-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of Gq-protein-dependent signals remain poorly understood. Here, using different experimental approaches, especially designer receptor exclusively activated by designer drug (DREADD) chemogenetic technology, we found that sustained activation of Gq-protein signaling impairs the functionality of striatal neurons and we unveil the precise molecular mechanism underlying this process: a phospholipase C/Ca2+/proline-rich tyrosine kinase 2/cJun N-terminal kinase pathway. Moreover, engagement of this intracellular signaling route was functionally active in the mouse dorsal striatum in vivo, as proven by the disruption of neuronal integrity and behavioral tasks. To analyze this effect anatomically, we manipulated Gq-protein-dependent signaling selectively in neurons belonging to the direct or indirect striatal pathway. Acute Gq-protein activation in direct-pathway or indirect-pathway neurons produced an enhancement or a decrease, respectively, of activity-dependent parameters. In contrast, sustained Gq-protein activation impaired the functionality of direct-pathway and indirect-pathway neurons and disrupted the behavioral performance and electroencephalography-related activity tasks controlled by either anatomical framework. Collectively, these findings define the molecular mechanism and functional relevance of Gq-protein-driven signals in striatal circuits under normal and overactivated states. SIGNIFICANCE STATEMENT: The dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. Whereas the Gs/Gi-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of Gq-protein-dependent signals remain unclear. Here, we show that striatal circuits can be 'turned on' by acute Gq-protein signaling or 'turned off' by sustained Gq-protein signaling. Specifically, sustained Gq-protein signaling inactivates striatal neurons by an intracellular pathway that relies on cJun N-terminal kinase. Overall, this study sheds new light onto the molecular mechanism and functional relevance of Gq-protein-driven signals in striatal circuits under normal and overactivated states.




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.




2016 | f1000res   IF 1.1
Cannabinoid receptor type-1: breaking the dogmas.
Busquets Garcia A, Soria-Gomez E, Bellocchio L, Marsicano G

Abstract:
The endocannabinoid system (ECS) is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB 1). In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells) and intracellular compartments (e.g., mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB 1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons). Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB 1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB 1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.




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.