Neurocentre Magendie

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24 publications


* equal contribution
Les IF indiqués ont été collectés par le Web of Sciences en Juin 2016

12/11/2016 | Brain Behav Immun   IF 5.9
Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis.
Planche V, Panatier A, Hiba B, Ducourneau EG, Raffard G, Dubourdieu N, Maitre M, Leste-Lasserre T, Brochet B, Dousset V, Desmedt A, Oliet SH, Tourdias T

Abstract:
Memory impairment is an early and disabling manifestation of multiple sclerosis whose anatomical and biological substrates are still poorly understood. We thus investigated whether memory impairment encountered at the early stage of the disease could be explained by a differential vulnerability of particular hippocampal subfields. By using experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, we identified that early memory impairment was associated with selective alteration of the dentate gyrus as pinpointed in vivo with diffusion-tensor-imaging (DTI). Neuromorphometric analyses and electrophysiological recordings confirmed dendritic degeneration, alteration in glutamatergic synaptic transmission and impaired long-term synaptic potentiation selectively in the dentate gyrus, but not in CA1, together with a more severe pattern of microglial activation in this subfield. Systemic injections of the microglial inhibitor minocycline prevented DTI, morphological, electrophysiological and behavioral impairments in EAE-mice. Furthermore, daily infusions of minocycline specifically within the dentate gyrus were sufficient to prevent memory impairment in EAE-mice while infusions of minocycline within CA1 were inefficient. We conclude that early memory impairment in EAE is due to a selective disruption of the dentate gyrus associated with microglia activation. These results open new pathophysiological, imaging, and therapeutic perspectives for memory impairment in multiple sclerosis.





01/08/2016 | Proc Natl Acad Sci U S A   IF 9.6
Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy.
Bassil F, Fernagut PO, Bezard E, Pruvost A, Leste-Lasserre T, Hoang QQ, Ringe D, Petsko GA, Meissner WG

Abstract:
Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (alpha-syn) aggregates in affected oligodendrocytes. Several studies point to alpha-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of alpha-syn in vitro and in neuronal cell models of alpha-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate alpha-syn pathology and to mediate neuroprotection in proteolipid protein alpha-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of alpha-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated alpha-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting alpha-syn accumulation.





20/05/2016 | Neuroscience   IF 3.2
Early GABAergic transmission defects in the external globus pallidus and rest/activity rhythm alteration in a mouse model of Huntington's disease.
Du Z, Chazalon M, Bestaven E, Leste-Lasserre T, Baufreton J, Cazalets JR, Cho YH, Garret M

Abstract:
Huntington's disease (HD) is characterized by progressive motor symptoms preceded by cognitive deficits and is regarded as a disorder that primarily affects the basal ganglia. The external globus pallidus (GPe) has a central role in the basal ganglia, projects directly to the cortex, and is majorly modulated by GABA. To gain a better understanding of the time course of HD progression and gain insight into the underlying mechanisms, we analysed GABAergic neurotransmission in the GPe of the R6/1 mouse model at purportedly asymptomatic and symptomatic stages (i.e., 2 and 6 months). Western blot and quantitative PCR analyses revealed alterations in the GPe of male R6/1 mice compared with wild type littermates. Expression of proteins involved in pre- and post-synaptic GABAergic compartments as well as synapse number were severely decreased at 2 and 6 months. At both ages, patch clamp electrophysiological recordings showed a decrease of spontaneous and miniature inhibitory post-synaptic currents suggesting that Huntington's disease mutation has an early effect on the GABA signalling in the brain. Therefore, we performed continuous locomotor activity recordings from 2 to 4 months of age. Actigraphy analyses revealed rest/activity fragmentation alterations that parallel GABAergic system impairment at 2 months, while the locomotor deficit is evident only at 3 months in R6/1 mice. Our results reveal early deficits in Huntington's disease and support growing evidence for a critical role played by the GPe in physiological and pathophysiological states. We suggest that actimetry may be used as a non-invasive tool to monitor early disease progression.





25/04/2015 | Hippocampus   IF 4.1
Adult-born dentate neurons are recruited in both spatial memory encoding and retrieval.
Tronel S, Charrier V, Sage C, Maitre M, Leste-Lasserre T, Abrous DN

Abstract:
Adult neurogenesis occurs in the dentate gyrus of the hippocampus, which is a key structure in learning and memory. Adult-generated granule cells have been shown to play a role in spatial memory processes such as acquisition or retrieval, in particular during an immature stage when they exhibit a period of increased plasticity. Here, we demonstrate that immature and mature neurons born in the dentate gyrus of adult rats are similarly activated in spatial memory processes. By imaging the activation of these two different neuron generations in the same rat and by using the immediate early gene Zif268, we show that these neurons are involved in both spatial memory acquisition and retrieval. These results demonstrate that adult-generated granule cells are involved in memory beyond their immaturity stage. This article is protected by copyright. All rights reserved.





02/12/2014 | Endocrinology   IF 4.2
Cannabinoid type 1 (CB) receptors on Sim1-expressing neurons regulate energy expenditure in male mice.
Cardinal P, Bellocchio L, Guzman-Quevedo O, Andre C, Clark S, Elie M, Leste-Lasserre T, Gonzales D, Cannich A, Marsicano G, Cota D

Abstract:
The paraventricular nucleus of the hypothalamus (PVN) regulates energy balance by modulating not only food intake, but also energy expenditure and brown adipose tissue (BAT) thermogenesis. To test the hypothesis that cannabinoid type 1 (CB1) receptor in PVN neurons might control these processes, we used the Cre/loxP system to delete CB1 from Single minded 1 (Sim1) neurons, which account for the majority of PVN neurons. On standard chow, mice lacking CB1 receptor in Sim1 neurons (Sim1-CB1-KO) had food intake, body weight, adiposity, glucose metabolism and energy expenditure comparable to wild-type (Sim1-CB1-WT) littermates. However, maintenance on a high-fat diet (HFD) revealed a gene-by-diet interaction whereby Sim1-CB1-KO mice had decreased adiposity, improved insulin sensitivity and increased energy expenditure, while feeding behavior was similar to Sim1-CB1-WT mice. Additionally, HFD-fed Sim1-CB1-KO mice had increased mRNA expression of the beta3-adrenergic receptor, as well as of UCP-1, Cox-IV and Tfam in the BAT, all molecular changes suggestive of increased thermogenesis. Pharmacological studies using beta-blockers suggested that modulation of beta-adrenergic transmission play an important role in determining energy expenditure changes observed in Sim1-CB1-KO. Finally, chemical sympathectomy abolished the obesity-resistant phenotype of Sim1-CB1-KO mice. Altogether, these findings reveal a diet-dependent dissociation in the CB1 receptor control of food intake and energy expenditure, likely mediated by the PVN, where CB1 receptors on Sim1-positive neurons do not impact food intake, but hinder energy expenditure during dietary environmental challenges that promote body weight gain.





10/2014 | Mol Metab   IF 5.4
CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin.
Cardinal P, Andre C, Quarta C, Bellocchio L, Clark S, Elie M, Leste-Lasserre T, Maitre M, Gonzales D, Cannich A, Pagotto U, Marsicano G, Cota D

Abstract:
Metabolic flexibility allows rapid adaptation to dietary change, however, little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.





25/07/2013 | Obesity (Silver Spring)   IF 3.4
Leucine supplementation modulates fuel substrates utilization and glucose metabolism in previously obese mice.
Binder E, Bermudez-Silva FJ, Elie M, Leste-Lasserre T, Belluomo I, Clark S, Duchampt A, Mithieux G, Cota D

Abstract:
OBJECTIVE: High-protein diets favor weight loss and its maintenance. Whether these effects might be recapitulated by certain amino acids is unknown. Therefore, the impact of leucine supplementation on energy balance and associated metabolic changes in diet-induced obese (DIO) mice during and after weight loss was investigated. DESIGN AND METHODS: DIO C57BL/6J mice were fed a normocaloric diet to induce weight loss while receiving or not the amino acid leucine in drinking water. Body weight, food intake, body composition, energy expenditure, glucose tolerance, insulin, and leptin sensitivity were evaluated. Q-PCR analysis was performed on muscle, brown and white adipose tissues. RESULTS: DIO mice decreased body weight and fat mass in response to chow, but supplementation with leucine did not affect these parameters. During weight maintenance, mice supplemented with leucine had improved glucose tolerance, increased leptin sensitivity, and lower respiratory quotient. The latter was associated with changes in the expression of several genes modulating fatty acid metabolism and mitochondrial activity in the epididymal white and the brown adipose tissues, but not muscle. CONCLUSIONS: Leucine supplementation might represent an adjuvant beneficial nutritional therapy during weight loss and maintenance, because it improves lipid and glucose metabolism and restores leptin sensitivity in previously obese animals.





19/03/2013 | Proc Natl Acad Sci U S A   IF 9.6
Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB(1) receptor blockade.
Bellocchio L, Soria-Gomez E, Quarta C, Metna-Laurent M, Cardinal P, Binder E, Cannich A, Delamarre A, Haring M, Martin-Fontecha M, Vega D, Leste-Lasserre T, Bartsch D, Monory K, Lutz B, Chaouloff F, Pagotto U, Guzman M, Cota D, Marsicano G

Abstract:
Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB1) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB1 receptor blockade, we combined the acute injection of the CB1 receptor antagonist rimonabant with the use of conditional CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of beta-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral beta-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.





2013 | PLoS ONE   IF 3.1
Leucine supplementation protects from insulin resistance by regulating adiposity levels.
Binder E, Bermudez-Silva FJ, Andre C, Elie M, Romero-Zerbo SY, Leste-Lasserre T, Belluomo L, Duchampt A, Clark S, Aubert A, Mezzullo M, Fanelli F, Pagotto U, Laye S, Mithieux G, Cota D

Abstract:
BACKGROUND: Leucine supplementation might have therapeutic potential in preventing diet-induced obesity and improving insulin sensitivity. However, the underlying mechanisms are at present unclear. Additionally, it is unclear whether leucine supplementation might be equally efficacious once obesity has developed. METHODOLOGY/PRINCIPAL FINDINGS: Male C57BL/6J mice were fed chow or a high-fat diet (HFD), supplemented or not with leucine for 17 weeks. Another group of HFD-fed mice (HFD-pairfat group) was food restricted in order to reach an adiposity level comparable to that of HFD-Leu mice. Finally, a third group of mice was exposed to HFD for 12 weeks before being chronically supplemented with leucine. Leucine supplementation in HFD-fed mice decreased body weight and fat mass by increasing energy expenditure, fatty acid oxidation and locomotor activity in vivo. The decreased adiposity in HFD-Leu mice was associated with increased expression of uncoupling protein 3 (UCP-3) in the brown adipose tissue, better insulin sensitivity, increased intestinal gluconeogenesis and preservation of islets of Langerhans histomorphology and function. HFD-pairfat mice had a comparable improvement in insulin sensitivity, without changes in islets physiology or intestinal gluconeogenesis. Remarkably, both HFD-Leu and HFD-pairfat mice had decreased hepatic lipid content, which likely helped improve insulin sensitivity. In contrast, when leucine was supplemented to already obese animals, no changes in body weight, body composition or glucose metabolism were observed. CONCLUSIONS/SIGNIFICANCE: These findings suggest that leucine improves insulin sensitivity in HFD-fed mice by primarily decreasing adiposity, rather than directly acting on peripheral target organs. However, beneficial effects of leucine on intestinal gluconeogenesis and islets of Langerhans's physiology might help prevent type 2 diabetes development. Differently, metabolic benefit of leucine supplementation is lacking in already obese animals, a phenomenon possibly related to the extent of the obesity before starting the supplementation.





2013 | Mol Metab   IF 5.4
Astroglial CB1 cannabinoid receptors regulate leptin signaling in mouse brain astrocytes.
Bosier B, Bellocchio L, Metna-Laurent M, Soria-Gomez E, Matias I, Hebert-Chatelain E, Cannich A, Maitre M, Leste-Lasserre T, Cardinal P, Mendizabal-Zubiaga J, Canduela MJ, Reguero L, Hermans E, Grandes P, Cota D, Marsicano G

Abstract:
Type-1 cannabinoid (CB1) and leptin (ObR) receptors regulate metabolic and astroglial functions, but the potential links between the two systems in astrocytes were not investigated so far. Genetic and pharmacological manipulations of CB1 receptor expression and activity in cultured cortical and hypothalamic astrocytes demonstrated that cannabinoid signaling controls the levels of ObR expression. Lack of CB1 receptors also markedly impaired leptin-mediated activation of signal transducers and activators of transcription 3 and 5 (STAT3 and STAT5) in astrocytes. In particular, CB1 deletion determined a basal overactivation of STAT5, thereby leading to the downregulation of ObR expression, and leptin failed to regulate STAT5-dependent glycogen storage in the absence of CB1 receptors. These results show that CB1 receptors directly interfere with leptin signaling and its ability to regulate glycogen storage, thereby representing a novel mechanism linking endocannabinoid and leptin signaling in the regulation of brain energy storage and neuronal functions.