Publications du Neurocentre Magendie

Les publications







IF du Neurocentre
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684 publications

* equal contribution
Les IF indiqués ont été collectés par le Web of Sciences en Juin 2018



11/2017 | Cell Calcium   IF 3.7
Dynamics of surface neurotransmitter receptors and transporters in glial cells: Single molecule insights.
Ciappelloni S, Murphy-Royal C, Dupuis JP, Oliet SHR, Groc L

Abstract:
The surface dynamics of neurotransmitter receptors and transporters, as well as ion channels, has been well-documented in neurons, revealing complex molecular behaviour and key physiological functions. However, our understanding of the membrane trafficking and dynamics of the signalling molecules located at the plasma membrane of glial cells is still in its infancy. Yet, recent breakthroughs in the field of glial cells have been obtained using combination of superresolution microscopy, single molecule imaging, and electrophysiological recordings. Here, we review our current knowledge on the surface dynamics of neurotransmitter receptors, transporters and ion channels, in glial cells. It has emerged that the brain cell network activity, synaptic activity, and calcium signalling, regulate the surface distribution and dynamics of these molecules. Remarkably, the dynamics of a given neurotransmitter receptor/transporter at the plasma membrane of a glial cell or neuron is unique, revealing the existence of cell-type specific regulatory pathways. Thus, investigating the dynamics of signalling proteins at the surface of glial cells will likely shed new light on our understanding of glial cell physiology and pathology.





31/10/2017 | Cereb Cortex   IF 6.3
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.





26/10/2017 | Gut   IF 17
Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling.
Javary J, Allain-Courtois N, Saucisse N, Costet P, Heraud C, Benhamed F, Pierre R, Bure C, Pallares-Lupon N, Do Cruzeiro M, Postic C, Cota D, Dubus P, Rosenbaum J, Benhamouche-Trouillet S

Abstract:
OBJECTIVE: The AAA+ ATPase Reptin is overexpressed in hepatocellular carcinoma and preclinical studies indicate that it could be a relevant therapeutic target. However, its physiological and pathophysiological roles in vivo remain unknown. This study aimed to determine the role of Reptin in mammalian adult liver. DESIGN AND RESULTS: We generated an inducible liver-specific Reptin knockout (RepinLKO ) mouse model. Following Reptin invalidation, mice displayed decreased body and fat mass, hypoglycaemia and hypolipidaemia. This was associated with decreased hepatic mTOR protein abundance. Further experiments in primary hepatocytes demonstrated that Reptin maintains mTOR protein level through its ATPase activity. Unexpectedly, loss or inhibition of Reptin induced an opposite effect on mTORC1 and mTORC2 signalling, with: (1) strong inhibition of hepatic mTORC1 activity, likely responsible for the reduction of hepatocytes cell size, for decreased de novo lipogenesis and cholesterol transcriptional programmes and (2) enhancement of mTORC2 activity associated with inhibition of the gluconeogenesis transcriptional programme and hepatic glucose production. Consequently, the role of hepatic Reptin in the pathogenesis of insulin resistance (IR) and non-alcoholic fatty liver disease consecutive to a high-fat diet was investigated. We found that Reptin deletion completely rescued pathological phenotypes associated with IR, including glucose intolerance, hyperglycaemia, hyperlipidaemia and hepatic steatosis. CONCLUSION: We show here that the AAA +ATPase Reptin is a regulator of mTOR signalling in the liver and global glucido-lipidic homeostasis. Inhibition of hepatic Reptin expression or activity represents a new therapeutic perspective for metabolic syndrome.





24/10/2017 | Nat Commun   IF 12.4
Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice.
Aloisi E, Le Corf K, Dupuis J, Zhang P, Ginger M, Labrousse V, Spatuzza M, Georg Haberl M, Costa L, Shigemoto R, Tappe-Theodor A, Drago F, Vincenzo Piazza P, Mulle C, Groc L, Ciranna L, Catania MV, Frick A

Abstract:
Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Here, we probed the consequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-aspartate receptor (NMDAR) function, and behavioral phenotypes in the second-generation Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr1 KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with a reduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-activated long-term depression, and NMDAR/hippocampus dependent cognitive deficits. These synaptic and behavioral phenomena were reversed by knocking down Homer1a in Fmr1 KO mice. Our study provides a mechanistic link between changes of mGluR5 dynamics and pathological phenotypes of FXS, unveiling novel targets for mGluR5-based therapeutics.







19/09/2017 | Cell Metab   IF 20.6
Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity.
Quarta C, Clemmensen C, Zhu Z, Yang B, Joseph SS, Lutter D, Yi CX, Graf E, Garcia-Caceres C, Legutko B, Fischer K, Brommage R, Zizzari P, Franklin BS, Krueger M, Koch M, Vettorazzi S, Li P, Hofmann SM, Bakhti M, Bastidas-Ponce A, Lickert H, Strom TM, Gailus-Durner V, Bechmann I, Perez-Tilve D, Tuckermann J, Hrabe de Angelis M, Sandoval D, Cota D, Latz E, Seeley RJ, Muller TD, DiMarchi RD, Finan B, Tschop MH

Abstract:
Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity.





19/09/2017 | Proc Natl Acad Sci U S A   IF 9.5
Temporal binding function of dorsal CA1 is critical for declarative memory formation.
Sellami A, Al Abed AS, Brayda-Bruno L, Etchamendy N, Valerio S, Oule M, Pantaleon L, Lamothe V, Potier M, Bernard K, Jabourian M, Herry C, Mons N, Piazza PV, Eichenbaum H, Marighetto A

Abstract:
Temporal binding, the process that enables association between discontiguous stimuli in memory, and relational organization, a process that enables the flexibility of declarative memories, are both hippocampus-dependent and decline in aging. However, how these two processes are related in supporting declarative memory formation and how they are compromised in age-related memory loss remain hypothetical. We here identify a causal link between these two features of declarative memory: Temporal binding is a necessary condition for the relational organization of discontiguous events. We demonstrate that the formation of a relational memory is limited by the capability of temporal binding, which depends on dorsal (d)CA1 activity over time intervals and diminishes in aging. Conversely, relational representation is successful even in aged individuals when the demand on temporal binding is minimized, showing that relational/declarative memory per se is not impaired in aging. Thus, bridging temporal intervals by dCA1 activity is a critical foundation of relational representation, and a deterioration of this mechanism is responsible for the age-associated memory impairment.





08/09/2017 | Sci Rep   IF 4.1
Spinal miRNA-124 regulates synaptopodin and nociception in an animal model of bone cancer pain.
Elramah S, Lopez-Gonzalez MJ, Bastide M, Dixmerias F, Roca-Lapirot O, Wielanek-Bachelet AC, Vital A, Leste-Lasserre T, Brochard A, Landry M, Favereaux A

Abstract:
Strong breakthrough pain is one of the most disabling symptoms of cancer since it affects up to 90% of cancer patients and is often refractory to treatments. Alteration in gene expression is a known mechanism of cancer pain in which microRNAs (miRNAs), a class of non-coding regulatory RNAs, play a crucial role. Here, in a mouse model of cancer pain, we show that miR-124 is down-regulated in the spinal cord, the first relay of the pain signal to the brain. Using in vitro and in vivo approaches, we demonstrate that miR-124 is an endogenous and specific inhibitor of synaptopodin (Synpo), a key protein for synaptic transmission. In addition, we demonstrate that Synpo is a key component of the nociceptive pathways. Interestingly, miR-124 was down-regulated in the spinal cord in cancer pain conditions, leading to an up-regulation of Synpo. Furthermore, intrathecal injections of miR-124 mimics in cancerous mice normalized Synpo expression and completely alleviated cancer pain in the early phase of the cancer. Finally, miR-124 was also down-regulated in the cerebrospinal fluid of cancer patients who developed pain, suggesting that miR-124 could be an efficient analgesic drug to treat cancer pain patients.





01/09/2017 | Neuropsychopharmacology   IF 6.5
CB1 Receptors Signaling in the Brain: Extracting Specificity from Ubiquity.
Busquets-Garcia A, Bains J, Marsicano G

Abstract:
Endocannabinoids (eCBs) are amongst the most ubiquitous signaling molecules in the nervous system. Over the past few decades, observations based on a large volume of work, first examining the pharmacological effects of exogenous cannabinoids, and then the physiological functions of eCBs, have directly challenged long-held and dogmatic views about communication, plasticity and behavior in the Central Nervous System (CNS). The eCBs and their cognate cannabinoid receptors exhibit a number of unique properties that distinguish them from the widely studied classical amino acid transmitters, neuropeptides and catecholamines. Although we now have a loose set of mechanistic rules based on experimental findings, new studies continue to reveal that our understanding of the endocannabinoid system (ECS) is continuously evolving and challenging long-held conventions. Here, we will briefly summarize findings on the current canonical view of the 'endocannabinoid system' and will address novel aspects that reveal how a nearly ubiquitous system can determine highly specific functions in the brain. In particular, we will focus on findings that push for an expansion of our ideas around long-held beliefs about eCB signaling that, whilst clearly true, may be contributing to an oversimplified perspective on how cannabinoid signaling at the microscopic level impacts behavior at the macroscopic level.Neuropsychopharmacology accepted article preview online, 01 September 2017. doi:10.1038/npp.2017.206.





09/2017 | anal bioanal chem   IF 3.3
Derivatization-free LC-MS/MS method for estrogen quantification in mouse brain highlights a local metabolic regulation after oral versus subcutaneous administration.
Lozan E, Shinkaruk S, Al Abed SA, Lamothe V, Potier M, Marighetto A, Schmitter JM, Bennetau-Pelissero C, Bure C

Abstract:
17beta-Estradiol (17beta-E2) is a steroid with pleiotropic actions. In addition to being a sexual hormone, it is also produced in the brain where it modulates the reproductive axis. It has been shown that 17beta-E2 also acts on synaptic plasticity and plays a role in neurological pathways and in neurodegenerative diseases. Assaying this steroid in the brain is thus interesting to improve our knowledge of 17beta-E2 effects in the brain. However, 17beta-E2 concentration in the central nervous system has been reported to be of a few nanograms per gram wet weight (nanomolar range concentration); therefore, its quantification requires both an efficient extraction process and a sensitive detection method. Herein is presented a derivatization-free procedure based on solid-phase extraction followed by LC-MS/MS analysis, targeted on 17beta-E2, its isomer17alpha-E2, and its metabolites estrone (E1) and estriol (E3). This extraction process allowed reaching 96% 17beta-E2 recovery from the mouse brain. Limit of detection (LOD) and limit of quantification (LOQ) values of 0.5 and 2.5 pmol mL(-1), respectively, were reached for both 17alpha-E2 and 17beta-E2. LOD values for E1 and E3 were 0.01 and 0.025 pmol mL(-1), respectively. The variation coefficients for intra- and inter-assays were 6 and 14%, respectively, for both estradiol forms. The method was applied to assess estrogen levels in the mouse brain and hippocampus after 17beta-E2 acute (subcutaneous injection) and chronic (drinking water) physiological administration. Total estrogen levels were determined after enzymatic deconjugation and compared to free estrogen levels. While 17alpha-E2 was not detected in biological samples, 17beta-E2 and metabolite measurements highlight a local biotransformation of estrogens after physiological administration via drinking water. Graphical abstract Method workflow: After oral or subcutaneous Estradiol administration, mouse brain or hippocampus was removed. Samples were homogenized and prepared according to a liquid-liquid extraction, followed by a solid-phase extraction. Then, LC-MS/MS was optimized to quantify 17ss-E2, its isomer17alpha-E2, its metabolites estrone (E1) and estriol (E3) and their conjugates.