Institute des Neurosciences Cellulaires et Integratives

Strasbourg, France

Institute des Neurosciences Cellulaires et Integratives

Strasbourg, France
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Cordero-Erausquin M.,Institute des Neurosciences Cellulaires et Integratives | Cordero-Erausquin M.,University of Strasbourg | Inquimbert P.,Institute des Neurosciences Cellulaires et Integratives | Inquimbert P.,University of Strasbourg | And 4 more authors.
Neuroscience | Year: 2016

The dorsal horn (DH) of the spinal cord receives a variety of sensory information arising from the inner and outer environment, as well as modulatory inputs from supraspinal centers. This information is integrated by the DH before being forwarded to brain areas where it may lead to pain perception. Spinal integration of this information relies on the interplay between different DH neurons forming complex and plastic neuronal networks. Elements of these networks are therefore potential targets for new analgesics and pain-relieving strategies. The present review aims at providing an overview of the current knowledge on these networks, with a special emphasis on those involving interlaminar communication in both physiological and pathological conditions © 2016 IBRO


Pawlowski S.A.,Institute des Neurosciences Cellulaires et Integratives | Gaillard S.,Institute des Neurosciences Cellulaires et Integratives | Ghorayeb I.,University of Bordeaux Segalen | Ribeiro-da-Silva A.,McGill University | And 3 more authors.
Journal of Neuroscience | Year: 2013

Endogenous acetylcholine (ACh) is a well-known modulator of nociceptive transmission in the spinal cord of rodents. It arises mainly from a sparse population of cholinergic interneurons located in the dorsal horn of the spinal cord. This population was thought to be absent from the spinal cord of monkey, what might suggest that spinal ACh would not be a relevant clinical target for pain therapy. In humans, however, pain responses can be modulated by spinal ACh, as evidenced by the increasingly used analgesic procedure (for postoperative and labor patients) consisting of the epidural injection of the acetylcholinesterase inhibitor neostigmine. The source and target of this ACh remain yet to be elucidated. In this study, we used an immunolabeling for choline acetyltransferase to demonstrate, for the first time, the presence of a plexus of cholinergic fibers in laminae II-III of the dorsal horn of the macaque monkey. Moreover, we show the presence of numerous cholinergic cell bodies within the same laminae and compared their density and morphological properties with those previously described in rodents. An electron microscopy analysis demonstrates that cholinergic boutons are presynaptic to dorsal horn neurons as well as to the terminals of sensory primary afferents, suggesting that they are likely to modulate incoming somatosensory information. Our data suggest that this newly identified dorsal horn cholinergic system in monkeys is the source of the ACh involved in the analgesic effects of epidural neostigmine and could bemorespecifically targeted for novel therapeutic strategies for pain management in humans. © 2013 the authors.


Cesana E.,University of Pavia | Cesana E.,University of Milan | Pietrajtis K.,Ecole Normale Superieure de Paris | Pietrajtis K.,French Institute of Health and Medical Research | And 12 more authors.
Journal of Neuroscience | Year: 2013

The function of inhibitory interneurons within brain microcircuits depends critically on the nature and properties of their excitatory synaptic drive. Golgi cells (GoCs) of the cerebellum inhibit cerebellar granule cells (GrCs) and are driven both by feedforward mossy fiber (mf) and feedback GrC excitation. Here, we have characterized GrC inputs to GoCs in rats and mice. We show that, during sustained mf discharge, synapses from local GrCs contribute equivalent charge to GoCs as mf synapses, arguing for the importance of the feedback inhibition. Previous studies predicted that GrC-GoC synapses occur predominantly between parallel fibers (pfs) and apical GoC dendrites in the molecular layer (ML). By combining EM and Ca2+ imaging, we now demonstrate the presence of functional synaptic contacts between ascending axons (aa) of GrCs and basolateral dendrites of GoCs in the granular layer (GL). Immunohistochemical quantification estimates these contacts to be ~400 per GoC. Using Ca2+ imaging to identify synaptic inputs, we show that EPSCs from aa and mf contacts in basolateral dendrites display similarly fast kinetics, whereas pf inputs in the ML exhibit markedly slower kinetics as they undergo strong filtering by apical dendrites. We estimate that approximately half of the local GrC contacts generate fast EPSCs, indicating their basolateral location in the GL. We conclude that GrCs, through their aa contacts onto proximal GoC dendrites, define a powerful feedback inhibitory circuit in the GL. © 2013 the authors.


Massotte D.,Institute des Neurosciences Cellulaires et Integratives
British Journal of Pharmacology | Year: 2015

Opioid receptors are highly homologous GPCRs that modulate brain function at all levels of neural integration, including autonomous, sensory, emotional and cognitive processing. Opioid receptors functionally interact in vivo, but the underlying mechanisms involving direct receptor-receptor interactions, affecting signalling pathways or engaging different neuronal circuits, remain unsolved. Heteromer formation through direct physical interaction between two opioid receptors or between an opioid receptor and a non-opioid one has been postulated and can be characterized by specific ligand binding, receptor signalling and trafficking properties. However, despite numerous studies in heterologous systems, evidence for physical proximity in vivo is only available for a limited number of opioid heteromers, and their physiopathological implication remains largely unknown mostly due to the lack of appropriate tools. Nonetheless, data collected so far using endogenous receptors point to a crucial role for opioid heteromers as a molecular entity that could underlie human pathologies such as alcoholism, acute or chronic pain as well as psychiatric disorders. Opioid heteromers therefore stand as new therapeutic targets for the drug discovery field. Linked Articles This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. © 2014 The British Pharmacological Society.


Simonneaux V.,Institute des Neurosciences Cellulaires et Integratives | Bur I.,Institute des Neurosciences Cellulaires et Integratives | Ancel C.,Institute des Neurosciences Cellulaires et Integratives | Ansel L.,Institute des Neurosciences Cellulaires et Integratives | Klosen P.,Institute des Neurosciences Cellulaires et Integratives
Progress in Brain Research | Year: 2012

Reproduction is a fundamental biological function ensuring individual descendant survival and species perpetuity. It is an energy-consuming process, and therefore, all underlying mechanisms have to work in synchrony to ensure reproductive success. Synchronization of reproductive activity with the best time of the day or the year is part of such adaptive processes. Recently, a neuropeptide named kisspeptin, synthesized in two discrete hypothalamic nuclei, the anteroventral periventricular nucleus and the arcuate nucleus, has been demonstrated to be a potent stimulator operating upstream of the gonadotropic axis. In this review, we show how kisspeptinergic neurons integrate daily and seasonal time cues to synchronize reproductive activity with the cycling environment. © 2012 Elsevier B.V.


Ghossoub R.,Aix - Marseille University | Lembo F.,Aix - Marseille University | Rubio A.,Aix - Marseille University | Gaillard C.B.,Aix - Marseille University | And 8 more authors.
Nature Communications | Year: 2014

Exosomes are small vesicles that are secreted by cells and act as mediators of cell to cell communication. Because of their potential therapeutic significance, important efforts are being made towards characterizing exosomal contents. However, little is known about the mechanisms that govern exosome biogenesis. We have recently shown that the exosomal protein syntenin supports exosome production. Here we identify the small GTPase ADP ribosylation factor 6 (ARF6) and its effector phospholipase D2 (PLD2) as regulators of syntenin exosomes. ARF6 and PLD2 affect exosomes by controlling the budding of intraluminal vesicles (ILVs) into multivesicular bodies (MVBs). ARF6 also controls epidermal growth factor receptor degradation, suggesting a role in degradative MVBs. Yet ARF6 does not affect HIV-1 budding, excluding general effects on Endosomal Sorting Complexes Required for Transport. Our study highlights a novel pathway controlling ILV budding and exosome biogenesis and identifies an unexpected role for ARF6 in late endosomal trafficking. © 2014 Macmillan Publishers Limited. All rights reserved.


Becker J.A.,University of Strasbourg | Becker J.A.,CNRS Physiology of Reproduction and Behaviors | Clesse D.,Institute des Neurosciences Cellulaires et Integratives | Spiegelhalter C.,University of Strasbourg | And 6 more authors.
Neuropsychopharmacology | Year: 2014

The etiology of Autism Spectrum Disorders (ASDs) remains largely unknown. Identifying vulnerability genes for autism represents a major challenge in the field and allows the development of animal models for translational research. Mice lacking the mu opioid receptor gene (Oprm1-/-) were recently proposed as a monogenic mouse model of autism, based on severe deficits in social behavior and communication skills. We confirm this hypothesis by showing that adult Oprm1-/- animals recapitulate core and multiple comorbid behavioral symptoms of autism and also display anatomical, neurochemical, and genetic landmarks of the disease. Chronic facilitation of mGluR4 signaling, which we identified as a novel pharmacological target in ASDs in these mice, was more efficient in alleviating behavioral deficits than the reference molecule risperidone. Altogether, our data provide first evidence that disrupted mu opioid receptor signaling is sufficient to trigger a comprehensive autistic syndrome, maybe through blunted social reward processes, and this mouse model opens promising avenues for therapeutic innovation. © 2014 American College of Neuropsychopharmacology. All rights reserved.


Petitjean H.,Institute des Neurosciences Cellulaires et Integratives | Petitjean H.,University of Strasbourg | Hugel S.,Institute des Neurosciences Cellulaires et Integratives | Barthas F.,Institute des Neurosciences Cellulaires et Integratives | And 7 more authors.
European Journal of Neuroscience | Year: 2014

Probenecid, an agonist of transient receptor vanilloid (TRPV) type 2, was used to evaluate the effects of TRPV2 activation on excitatory and inhibitory synaptic transmission in the dorsal horn (DH) of the rat spinal cord and on nociceptive reflexes induced by thermal heat and mechanical stimuli. The effects of probenecid were compared with those of capsaicin, a TRPV1 agonist. Calcium imaging experiments on rat dorsal root ganglion (DRG) and DH cultures indicated that functional TRPV2 and TRPV1 were expressed by essentially non-overlapping subpopulations of DRG neurons, but were absent from DH neurons and DH and DRG glial cells. Pretreatment of DRG cultures with small interfering RNAs against TRPV2 suppressed the responses to probenecid. Patch-clamp recordings from spinal cord slices showed that probenecid and capsaicin increased the frequencies of spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents in a subset of laminae III-V neurons. In contrast to capsaicin, probenecid failed to stimulate synaptic transmission in lamina II. Intrathecal or intraplantar injections of probenecid induced mechanical hyperalgesia/allodynia without affecting nociceptive heat responses. Capsaicin induced both mechanical hyperalgesia/allodynia and heat hyperalgesia. Activation of TRPV1 or TRPV2 in distinct sets of primary afferents increased the sEPSC frequencies in a largely common population of DH neurons in laminae III-V, and might underlie the development of mechanical hypersensitivity following probenecid or capsaicin treatment. However, only TRPV1-expressing afferents facilitated excitatory and/or inhibitory transmission in a subpopulation of lamina II neurons, and this phenomenon might be correlated with the induction of thermal heat hyperalgesia. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.


Inquimbert P.,Institute des Neurosciences Cellulaires et Integratives
Journal of visualized experiments : JoVE | Year: 2013

Intraparenchymal injection of a viral vector enables conditional gene manipulation in distinct populations of neurons or particular regions of the central nervous system. We demonstrate a stereotaxic injection technique that allows targeted gene expression or silencing in the dorsal horn of the mouse spinal cord. The surgical procedure is brief. It requires laminectomy of a single vertebra, providing for quick recovery of the animal and unimpaired motility of the spine. Controlled injection of a small vector suspension volume at low speed and use of a microsyringe with beveled glass cannula minimize the tissue lesion. The local immune response to the vector depends on the intrinsic properties of the virus employed; in our experience, it is minor and short-lived when a recombinant adeno-associated virus is used. A reporter gene such as enhanced green fluorescent protein facilitates monitoring spatial distribution of the vector, and the efficacy and cellular specificity of the transfection.


PubMed | Institute des Neurosciences Cellulaires et Integratives
Type: Journal Article | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2013

Endogenous acetylcholine (ACh) is a well-known modulator of nociceptive transmission in the spinal cord of rodents. It arises mainly from a sparse population of cholinergic interneurons located in the dorsal horn of the spinal cord. This population was thought to be absent from the spinal cord of monkey, what might suggest that spinal ACh would not be a relevant clinical target for pain therapy. In humans, however, pain responses can be modulated by spinal ACh, as evidenced by the increasingly used analgesic procedure (for postoperative and labor patients) consisting of the epidural injection of the acetylcholinesterase inhibitor neostigmine. The source and target of this ACh remain yet to be elucidated. In this study, we used an immunolabeling for choline acetyltransferase to demonstrate, for the first time, the presence of a plexus of cholinergic fibers in laminae II-III of the dorsal horn of the macaque monkey. Moreover, we show the presence of numerous cholinergic cell bodies within the same laminae and compared their density and morphological properties with those previously described in rodents. An electron microscopy analysis demonstrates that cholinergic boutons are presynaptic to dorsal horn neurons as well as to the terminals of sensory primary afferents, suggesting that they are likely to modulate incoming somatosensory information. Our data suggest that this newly identified dorsal horn cholinergic system in monkeys is the source of the ACh involved in the analgesic effects of epidural neostigmine and could be more specifically targeted for novel therapeutic strategies for pain management in humans.

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