Neurocentre Magendie

Les publications







IF du Neurocentre
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701 publications

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



31/05/2016 | Neuropharmacology   IF 4.9
Differential control of dopamine ascending pathways by serotonin2B receptor antagonists: New opportunities for the treatment of schizophrenia.
Devroye C, Cathala A, Haddjeri N, Rovera R, Vallee M, Drago F, Piazza PV, Spampinato U

Abstract:
Recent studies suggest that the central serotonin2B receptor (5-HT2BR) could be an interesting pharmacological target for treating neuropsychiatric disorders related to dopamine (DA) dysfunction, such as schizophrenia. Thus, the present study was aimed at characterizing the role of 5-HT2BRs in the control of ascending DA pathway activity. Using neurochemical, electrophysiological and behavioral approaches, we assessed the effects of two selective 5-HT2BR antagonists, RS 127445 and LY 266097, on in vivo DA outflow in DA-innervated regions, on mesencephalic DA neuronal firing, as well as in behavioral tests predictive of antipsychotic efficacy and tolerability, such as phencyclidine (PCP)-induced deficit in novel object recognition (NOR) test, PCP-induced hyperlocomotion and catalepsy. Both RS 127445 (0.16 mg/kg, i.p.) and LY 266097 (0.63 mg/kg, i.p.) increased DA outflow in the medial prefrontal cortex (mPFC). RS 127445, devoid of effect in the striatum, decreased DA outflow in the nucleus accumbens, and potentiated haloperidol (0.1 mg/kg, s.c.)-induced increase in mPFC DA outflow. Also, RS 127445 decreased the firing rate of DA neurons in the ventral tegmental area, but had no effect in the substantia nigra pars compacta. Finally, both RS 127445 and LY 266097 reversed PCP-induced deficit in NOR test, and reduced PCP-induced hyperlocomotion, without inducing catalepsy. These results demonstrate that 5-HT2BRs exert a differential control on DA pathway activity, and suggest that 5-HT2BR antagonists could represent a new class of drugs for improved treatment of schizophrenia, with an ideal profile of effects expected to alleviate cognitive and positive symptoms, without eliciting extrapyramidal symptoms.





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.





21/03/2016 | Psychoneuroendocrinology   IF 4.2
Estradiol enhances retention but not organization of hippocampus-dependent memory in intact male mice.
Al Abed AS, Sellami A, Brayda-Bruno L, Lamothe V, Nogues X, Potier M, Bennetau-Pelissero C, Marighetto A

Abstract:
Because estrogens have mostly been studied in gonadectomized females, effects of chronic exposure to environmental estrogens in the general population are underestimated. Estrogens can enhance hippocampus-dependent memory through the modulation of information storage. However, declarative memory, the hippocampus-dependent memory of facts and events, demands more than abilities to retain information. Specifically, memory of repetitive events of everyday life such as 'where I parked' requires abilities to organize/update memories to prevent proactive interference from similar memories of previous 'parking events'. Whether such organizational processes are estrogen-sensitive is unknown. We here studied, in intact young and aged adult mice, drinking-water (1muM) estradiol effects on both retention and organizational components of hippocampus-dependent memory, using a radial-maze task of everyday-like memory. Demand on retention vs organization was manipulated by varying the time-interval separating repetitions of similar events. Estradiol increased performance in young and aged mice under minimized organizational demand, but failed to improve the age-associated memory impairment and diminished performance in young mice under high organizational demand. In fact, estradiol prolonged mnemonic retention of successive events without improving organization abilities, hence resulted in more proactive interference from irrelevant memories. c-Fos imaging of testing-induced brain activations showed that the deterioration of young memory was associated with dentate gyrus dysconnectivity, reminiscent of that seen in aged mice. Our findings support the view that estradiol is promnesic but also reveal that such property can paradoxically impair memory. These findings have important outcomes regarding health issues relative to the impact of environmental estrogens in the general population.





15/02/2016 | Nat Neurosci   IF 16.7
4-Hz oscillations synchronize prefrontal-amygdala circuits during fear behavior.
Karalis N, Dejean C, Chaudun F, Khoder S, Rozeske RR, Wurtz H, Bagur S, Benchenane K, Sirota A, Courtin J, Herry C

Abstract:
Fear expression relies on the coordinated activity of prefrontal and amygdala circuits, yet the mechanisms allowing long-range network synchronization during fear remain unknown. Using a combination of extracellular recordings, pharmacological and optogenetic manipulations, we found that freezing, a behavioral expression of fear, temporally coincided with the development of sustained, internally generated 4-Hz oscillations in prefrontal-amygdala circuits. 4-Hz oscillations predict freezing onset and offset and synchronize prefrontal-amygdala circuits. Optogenetic induction of prefrontal 4-Hz oscillations coordinates prefrontal-amygdala activity and elicits fear behavior. These results unravel a sustained oscillatory mechanism mediating prefrontal-amygdala coupling during fear behavior.





01/01/2016 | dis model mech   IF 4.3
The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice.
Bermudez-Silva FJ, Romero-Zerbo SY, Haissaguerre M, Ruz-Maldonado I, Lhamyani S, El Bekay R, Tabarin A, Marsicano G, Cota D

Abstract:
The endocannabinoid system (ECS) is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the beta-cell mass. The downstream signalling pathways mediating these effects are poorly understood. Mammalian target of rapamycin complex 1 (mTORC1) signalling is a key intracellular pathway involved in energy homeostasis and is known to importantly affect the physiology of pancreatic islets. We investigated the possible relationship between cannabinoid type 1 (CB1) receptor signalling and the mTORC1 pathway in the endocrine pancreas of mice by using pharmacological analysis as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, the kinase p70S6K1. In vitro static secretion experiments on islets, western blotting, and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS) at 0.1 microM while increasing phosphorylation of p70S6K1 and ribosomal protein S6 (rpS6) within the islets. Specific pharmacological blockade of mTORC1 by 3 nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3 mg/kg body weight rimonabant decreased insulin levels and induced glucose intolerance in lean mice without altering peripheral insulin sensitivity; this effect was prevented by peripheral administration of low doses of rapamycin (0.1 mg/kg body weight), which increased insulin sensitivity. These findings suggest a functional interaction between the ECS and the mTORC1 pathway within the endocrine pancreas and at the whole-organism level, which could have implications for the development of new therapeutic approaches for pancreatic beta-cell diseases.





2016 | Sci Rep
Layer-specific potentiation of network GABAergic inhibition in the CA1 area of the hippocampus.
Colavita M, Terral G, Lemercier CE, Drago F, Marsicano G, Massa F

Abstract:
One of the most important functions of GABAergic inhibition in cortical regions is the tight control of spatiotemporal activity of principal neuronal ensembles. However, electrophysiological recordings do not provide sufficient spatial information to determine the spatiotemporal properties of inhibitory plasticity. Using Voltage Sensitive Dye Imaging (VSDI) in mouse hippocampal slices, we demonstrate that GABAA-mediated field inhibitory postsynaptic potentials undergo layer-specific potentiation upon activation of metabotropic glutamate receptors (mGlu). VSDI recordings allowed detection of pharmacologically isolated GABAA-dependent hyperpolarization signals. Bath-application of the selective group-I mGlu receptor agonist, (S)-3,5-Dihydroxyphenylglycine (DHPG), induces an enhancement of the GABAergic VSDI-recorded signal, which is more or less pronounced in different hippocampal layers. This potentiation is mediated by mGlu5 and downstream activation of IP3 receptors. Our results depict network GABAergic activity in the hippocampal CA1 region and its sub-layers, showing also a novel form of inhibitory synaptic plasticity tightly coupled to glutamatergic activity.





Abstract:
Hypothalamic neurohormones are released in a pulsatile manner. The mechanisms of this pulsatility remain poorly understood and several hypotheses are available, depending upon the neuroendocrine system considered. Among these systems, hypothalamo-neurohypophyseal magnocellular neurons have been early-considered models, as they typically display an electrical activity consisting of bursts of action potentials that is optimal for the release of boluses of the neurohormones oxytocin and vasopressin. The cellular mechanisms underlying this bursting behavior have been studied in vitro, using either acute slices of the adult hypothalamus, or organotypic cultures of neonatal hypothalamic tissue. We have recently proposed, from experiments in organotypic cultures, that specific central pattern generator networks, upstream of magnocellular neurons, determine their bursting activity. Here, we have tested whether a similar hypothesis can be derived from in vitro experiments in acute slices of the adult hypothalamus. To this aim we have screened our electrophysiological recordings of the magnocellular neurons, previously obtained from acute slices, with an analysis of autocorrelation of action potentials to detect a rhythmic drive as we recently did for organotypic cultures. This confirmed that the bursting behavior of magnocellular neurons is governed by central pattern generator networks whose rhythmic drive, and thus probably integrity, is however less satisfactorily preserved in the acute slices from adult brains.





Abstract:
Extensive evidence suggests that long term dietary n-3 polyunsaturated fatty acids (PUFAs) deficiency results in altered emotional behaviour. We have recently demonstrated that n-3 PUFAs deficiency induces emotional alterations through abnormal corticosterone secretion which leads to altered dendritic arborisation in the prefrontal cortex (PFC). Here we show that hypothalamic-pituitary-adrenal (HPA) axis feedback inhibition was not compromised in n-3 deficient mice. Rather, glucocorticoid receptor (GR) signaling pathway was inactivated in the PFC but not in the hippocampus of n-3 deficient mice. Consequently, only dendritic arborisation in PFC was affected by dietary n-3 PUFAs deficiency. In addition, occlusion experiment with GR blockade altered GR signaling in the PFC of control mice, with no further alterations in n-3 deficient mice. In conclusion, n-3 PUFAs deficiency compromised PFC, leading to dendritic atrophy, but did not change hippocampal GR function and dendritic arborisation. We argue that this GR sensitivity contributes to n-3 PUFAs deficiency-related emotional behaviour deficits.





2016 | f1000res
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.





2016 | PLoS ONE   IF 3.1
LAMP5 Fine-Tunes GABAergic Synaptic Transmission in Defined Circuits of the Mouse Brain.
Tiveron MC, Beurrier C, Ceni C, Andriambao N, Combes A, Koehl M, Maurice N, Gatti E, Abrous DN, Kerkerian-Le Goff L, Pierre P, Cremer H

Abstract:
LAMP5 is member of the LAMP family of membrane proteins. In contrast to the canonical members of this protein family, LAMP1 and LAMP2, which show widespread expression in many tissues, LAMP 5 is brain specific in mice. In C. elegans, the LAMP5 ortholog UNC-46 has been suggested to act a trafficking chaperone, essential for the correct targeting of the nematode vesicular GABA-transporter UNC-47. We show here that in the mouse brain LAMP5 is expressed in subpopulations of GABAergic forebrain neurons in the striato-nigral system and the olfactory bulb. The protein was present at synaptic terminals, overlapping with the mammalian vesicular GABA-transporter VGAT. In LAMP5-deficient mice localization of the transporter was unaffected arguing against a conserved role in VGAT trafficking. Electrophysiological analyses in mutants showed alterations in short term synaptic plasticity suggesting that LAMP5 is involved in controlling the dynamics of evoked GABAergic transmission. At the behavioral level, LAMP5 mutant mice showed decreased anxiety and deficits in olfactory discrimination. Altogether, this work implicates LAMP5 function in GABAergic neurotransmission in defined neuronal subpopulations.