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42 Publication(s) (2602 dans la base de données)
Carta M, Opazo P, Veran J, Athané A, Choquet D, Coussen F, Mulle C. CaMKII-dependent phosphorylation of GluK5 mediates plasticity of kainate receptors. EMBO J. 2013 Jan 4. 2013
original article. IF : 9.205
Liens vers résumé
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| Unité |
Institut Interdisciplinaire de Neurosciences - Daniel Choquet |
| Equipe |
Physiologie des synapses glutamatergiques - Christophe Mulle |
| Axe de recherche |
Synapse ; Neurobiologie du développement |
| Abstract |
Calmodulin-dependent kinase II (CaMKII) is key for long-term potentiation of synaptic AMPA receptors. Whether CaMKII is involved in activity-dependent plasticity of other ionotropic glutamate receptors is unknown. We show that repeated pairing of pre- and postsynaptic stimulation at hippocampal mossy fibre synapses induces long-term depression of kainate receptor (KAR)-mediated responses, which depends on Ca(2+) influx, activation of CaMKII, and on the GluK5 subunit of KARs. CaMKII phosphorylation of three residues in the C-terminal domain of GluK5 subunit markedly increases lateral mobility of KARs, possibly by decreasing the binding of GluK5 to PSD-95. CaMKII activation also promotes surface expression of KARs at extrasynaptic sites, but concomitantly decreases its synaptic content. Using a molecular replacement strategy, we demonstrate that the direct phosphorylation of GluK5 by CaMKII is necessary for KAR-LTD. We propose that CaMKII-dependent phosphorylation of GluK5 is responsible for synaptic depression by untrapping of KARs from the PSD and increased diffusion away from synaptic sites. |
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Lanore F, Labrousse VF, Szabo Z, Normand E, Blanchet C, Mulle C. Deficits in morphofunctional maturation of hippocampal mossy fiber synapses in a mouse model of intellectual disability. J Neurosci. 2012 Dec 5;32(49):17882-93. 2012
original article. IF : 7.115
Liens vers résumé
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| Unité |
Institut Interdisciplinaire de Neurosciences - Daniel Choquet |
| Equipe |
Physiologie des synapses glutamatergiques - Christophe Mulle |
| Axe de recherche |
Synapse ; Neurobiologie du développement |
| Abstract |
The grik2 gene, coding for the kainate receptor subunit GluK2 (formerly GluR6), is associated with autism spectrum disorders and intellectual disability. Here, we tested the hypothesis that GluK2 could play a role in the appropriate maturation of synaptic circuits involved in learning and memory. We show that both the functional and morphological maturation of hippocampal mossy fiber to CA3 pyramidal cell (mf-CA3) synapses is delayed in mice deficient for the GluK2 subunit (GluK2(-/-)). In GluK2(-/-) mice this deficit is manifested by a transient reduction in the amplitude of AMPA-EPSCs at a critical time point of postnatal development, whereas the NMDA component is spared. By combining multiple probability peak fluctuation analysis and immunohistochemistry, we have provided evidence that the decreased amplitude reflects a decrease in the quantal size per mf-CA3 synapse and in the number of active synaptic sites. Furthermore, we analyzed the time course of structural maturation of CA3 synapses by confocal imaging of YFP-expressing cells followed by tridimensional (3D) anatomical reconstruction of thorny excrescences and presynaptic boutons. We show that major changes in synaptic structures occur subsequently to the sharp increase in synaptic transmission, and more importantly that the course of structural maturation of synaptic elements is impaired in GluK2(-/-) mice. This study highlights how a mutation in a gene linked to intellectual disability in the human may lead to a transient reduction of synaptic strength during postnatal development, impacting on the proper formation of neural circuits linked to memory. |
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Veran J, Kumar J, Pinheiro PS, Athané A, Mayer ML, Perrais D, Mulle C. Zinc Potentiates GluK3 Glutamate Receptor Function by Stabilizing the Ligand Binding Domain Dimer Interface. Neuron. 2012 Nov 8;76(3):565-78. 2012
IF : 14.736
Liens vers résumé
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| Unité |
Institut Interdisciplinaire de Neurosciences - Daniel Choquet |
| Equipe |
Physiologie des synapses glutamatergiques - Christophe Mulle |
| Axe de recherche |
Synapse ; Neurobiologie du développement |
| Abstract |
Kainate receptors (KARs) play a key role in the regulation of synaptic networks. Here, we show that zinc, a cation released at a subset of glutamatergic synapses, potentiates glutamate currents mediated by homomeric and heteromeric KARs containing GluK3 at 10-100 μM concentrations, whereas it inhibits other KAR subtypes. Potentiation of GluK3 currents is mainly due to reduced desensitization, as shown by kinetic analysis and desensitization mutants. Crystallographic and mutation analyses revealed that a specific zinc binding site is formed at the base of the ligand binding domain (LBD) dimer interface by a GluK3-specific aspartate (Asp759), together with two conserved residues, His762 and Asp730, the latter located on the partner subunit. In addition, we propose that tetrameric GluK2/GluK3 receptors are likely assembled as pairs of heterodimeric LBDs. Therefore, zinc binding stabilizes the labile GluK3 dimer interface, slows desensitization, and potentiates currents, providing a mechanism for KAR potentiation at glutamatergic synapses. |
| Publication principale |
oui |
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Gelsomino G, Menna E, Antonucci F, Rodighiero S, Riganti L, Mulle C, Benfenati F, Valtorta F, Verderio C, Matteoli M. Kainate Induces Mobilization of Synaptic Vesicles at the Growth Cone through the Activation of Protein Kinase A. Cereb Cortex. 2012 Mar 7. 2012
original article. IF : 6.844
Liens vers résumé
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| Unité |
Institut Interdisciplinaire de Neurosciences - Daniel Choquet |
| Equipe |
Physiologie des synapses glutamatergiques - Christophe Mulle |
| Axe de recherche |
Synapse ; Neurobiologie du développement |
| Collaboration européenne |
- Department of Medical Pharmacology and Consiglio Nazionale delle Ricerche (CNR) Institute of Neuroscience, University of Milano, 20129 Milano, Italy
- Department of Neuroscience and Brain Technologies, The Italian Institute of Technology and Dipartimento di Medicina Sperimentale, University of Genova, 16163 Genova, Italy
- San Raffaele Scientific Institute, Vita-Salute University, 20132 Milano, Italy
- Fondazione Filarete, 20139 Milano, Italy
- Istituto Clinico Humanitas, Istituto di ricovero e cura a carattere scientifico (IRCCS), 20089 Rozzano, Italy
- Current address: CNR, Institute of Molecular Bioimaging and Physiology, 20090 Segrate, Milano, Italy |
| Abstract |
Activation of protein kinase A (PKA) pathway at presynaptic terminals plays a crucial role in the supply of synaptic vesicles (SVs) from the reserve pool, affecting the steady-state level of activity and the reconstitution of the readily releasable pool after intense stimulation. However, the identity of the stimuli activating this pathway is undefined. Using fluorescence resonance energy transfer and molecular genetic, we show that kainate, through the activation of presynaptic kainate receptors, induces PKA activation and enhances synapsin I phosphorylation at PKA-specific residues. This leads to a dispersion of synapsin I immunoreactivity, which is accompanied by a PKA-dependent increase in the rate of SV recycling at the growth cone and by an enhanced miniature excitatory postsynaptic currents frequency in mature networks. Selective activation of this pathway is induced by the native neurotransmitter glutamate, when applied in the high nanomolar range. These data identify glutamate, specifically acting on KARs, as one of the stimuli able to induce phosphorylation of synapsin at PKA sites, both at the axonal growth cone and at the mature synapse, thus increasing SV availability and contributing to plasticity phenomena. |
| Publication principale |
oui |
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Pinheiro PS, Lanore F, Veran J, Artinian J, Blanchet C, Crépel V, Perrais D, Mulle C. Selective Block of Postsynaptic Kainate Receptors Reveals Their Function at Hippocampal Mossy Fiber Synapses.
Cereb Cortex. 2012 Feb 17. 2012
original article. IF : 6.844
Liens vers résumé
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| Unité |
Institut Interdisciplinaire de Neurosciences - Daniel Choquet |
| Equipe |
Physiologie des synapses glutamatergiques - Christophe Mulle |
| Axe de recherche |
Synapse ; Neurobiologie du développement |
| Collaboration nationale |
- INMED, INSERM U901, Université de La Méditerranée, Parc scientifique de Luminy, BP 13, 13273 Marseille Cedex 09, France
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| Collaboration européenne |
- Current address: Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark |
| Abstract |
Progress in understanding the roles of kainate receptors (KARs) in synaptic integration, synaptic networks, and higher brain function has been hampered by the lack of selective pharmacological tools. We have found that UBP310 and related willardiine derivatives, previously characterized as selective GluK1 and GluK3 KAR antagonists, block postsynaptic KARs at hippocampal mossy fiber (MF) CA3 synapses while sparing AMPA and NMDA receptors. We further show that UBP310 is an antagonist of recombinant GluK2/GluK5 receptors, the major population of KARs in the brain. Postsynaptic KAR receptor blockade at MF synapses significantly reduces the sustained depolarization, which builds up during repetitive activity, and impacts on spike transmission mediated by heterosynaptic signals. In addition, KARs present in aberrant MF synapses in the epileptic hippocampus were also blocked by UBP310. Our results support a specific role for postsynaptic KARs in synaptic integration of CA3 pyramidal cells and describe a tool that will be instrumental in understanding the physiopathological role of KARs in the brain |
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Caiati MD, Sivakumaran S, Lanore F, Mulle C, Richard E, Verrier D, Marsicano G, Miles R, Cherubini E. Developmental regulation of CB1-mediated spike-time dependent depression at immature mossy fiber-CA3 synapses. Sci Rep. 2012;2:285. Epub 2012 Feb 24. 2012
Liens vers résumé
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| Unité |
Neurocentre Magendie - Physiopathologie de la plasticité neuronale - Pier Vincenzo Piazza ; Institut Interdisciplinaire de Neurosciences - Daniel Choquet |
| Equipe |
Endocannabinoïdes et neuroadaptation - Giovanni Marsicano ; Physiologie des synapses glutamatergiques - Christophe Mulle |
| Axe de recherche |
Synapse |
| Collaboration nationale |
- INSERM UMRS975, Paris, France |
| Collaboration européenne |
- Neurobiology Dept. and Italian Institute of Technology Unit, International School for Advanced Studies, Trieste, Italy |
| Abstract |
Early in postnatal life, mossy fibres (MF), the axons of granule cells in the dentate gyrus, release GABA which is depolarizing and excitatory. Synaptic currents undergo spike-time dependent long-term depression (STD-LTD) regardless of the temporal order of stimulation (pre versus post and viceversa). Here we show that at P3 but not at P21, STD-LTD, induced by negative pairing, is mediated by endocannabinoids mobilized from the postsynaptic cell during spiking-induced membrane depolarization. By diffusing backward, endocannabinoids activate cannabinoid type-1 (CB1) receptors probably expressed on MF. Thus, STD-LTD was prevented by CB1 receptor antagonists and was absent in CB1-KO mice. Consistent with these data, in situ hybridization experiments revealed detectable level of CB1 mRNA in the granule cell layer at P3 but not at P21. These results indicate that CB1 receptors are transiently expressed on immature MF terminals where they counteract the enhanced neuronal excitability induced by the excitatory action of GABA. |
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Bénard G, Massa F, Puente N, Lourenço J, Bellocchio L, Soria-Gómez E, Matias I, Delamarre A, Metna-Laurent M, Cannich A, Hebert-Chatelain E, Mulle C, Ortega-Gutiérrez S, Martín-Fontecha M, Klugmann M, Guggenhuber S, Lutz B, Gertsch J, Chaouloff F, López-Rodríguez ML, Grandes P, Rossignol R, Marsicano G.
Mitochondrial CB(1) receptors regulate neuronal energy metabolism. Nat Neurosci. 2012 Mar 4. 2012
original article. IF : 14.191
Liens vers résumé
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| Unité |
Neurocentre Magendie - Physiopathologie de la plasticité neuronale - Pier Vincenzo Piazza ; Institut Interdisciplinaire de Neurosciences - Daniel Choquet |
| Equipe |
Endocannabinoïdes et neuroadaptation - Equipe AVENIR - Giovanni Marsicano ; Physiologie des synapses glutamatergiques - Christophe Mulle |
| Axe de recherche |
Cognition normale et pathologique ; Neuropsychopharmacologie et thérapeutiques des déficits - axe transversal ; Neurobiologie du développement ; Synapse |
| Collaboration nationale |
- Université de Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), EA 4576, Bordeaux, France. |
| Collaboration européenne |
-Department of Neurosciences, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain.
-Department of Organic Chemistry, Complutense University, Madrid, Spain.
-Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
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| Collaboration internationale |
- Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
- Institute of Biochemistry and Molecular Medicine, Bern, Switzerland. |
| Abstract |
The mammalian brain is one of the organs with the highest energy demands, and mitochondria are key determinants of its functions. Here we show that the type-1 cannabinoid receptor (CB(1)) is present at the membranes of mouse neuronal mitochondria (mtCB(1)), where it directly controls cellular respiration and energy production. Through activation of mtCB(1) receptors, exogenous cannabinoids and in situ endocannabinoids decreased cyclic AMP concentration, protein kinase A activity, complex I enzymatic activity and respiration in neuronal mitochondria. In addition, intracellular CB(1) receptors and mitochondrial mechanisms contributed to endocannabinoid-dependent depolarization-induced suppression of inhibition in the hippocampus. Thus, mtCB(1) receptors directly modulate neuronal energy metabolism, revealing a new mechanism of action of G protein-coupled receptor signaling in the brain. |
| Publication principale |
oui |
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Santos SD, Iuliano O, Ribeiro L, Veran J, Ferreira JS, Rio P, Mulle C, Duarte CB, Carvalho AL. Contactin associated protein 1 (Caspr1) regulates the traffic and synaptic content of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors.
J Biol Chem. 2012 Jan 5 . 2012
original article. IF : 5.328
Liens vers résumé
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| Unité |
Institut Interdisciplinaire de Neurosciences - Daniel Choquet |
| Equipe |
Physiologie des synapses glutamatergiques - Christophe Mulle |
| Axe de recherche |
Synapse |
| Collaboration européenne |
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal
- The Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal |
| Abstract |
Glutamate receptors of the AMPA-type mediate fast excitatory synaptic transmission in the CNS. Synaptic strength is modulated by AMPA receptor binding partners, which regulate receptor synaptic targeting and functional properties. We identify Contactin associated protein 1 (Caspr1) as an AMPA receptor interactor. Caspr1 is present in synapses, and interacts with AMPA receptors in brain synaptic fractions. Co-expression of Caspr1 with GluA1 increases the amplitude of glutamate-evoked currents. Caspr1 overexpression in hippocampal neurons increases the number and size of synaptic GluA1 clusters, whereas knockdown of Caspr1 decreases the intensity of synaptic GluA1 clusters. Hence, Caspr1 is a regulator of the trafficking of AMPA receptors to synapses. |
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Huyghe D, Veran J, Labrousse VF, Perrais D, Mulle C, Coussen F. Endocytosis of the Glutamate Receptor Subunit GluK3 Controls Polarized Trafficking. J Neurosci. 2011 Aug 10;31(32):11645-54. 2011
original article. IF : 7.271
Liens vers résumé
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| Unité |
Institut Interdisciplinaire de Neurosciences - Daniel Choquet |
| Equipe |
Physiologie des synapses glutamatergiques - Christophe Mulle |
| Axe de recherche |
Synapse ; Neurobiologie du développement |
| Abstract |
Kainate receptors (KARs) are widely expressed in the brain and are present at both presynaptic and postsynaptic sites. GluK3-containing KARs are thought to compose presynaptic autoreceptors that facilitate hippocampal mossy fiber synaptic transmission. Here we identify molecular mechanisms that underlie the polarized trafficking of KARs composed of the GluK3b splice variant. Endocytosis followed by degradation is driven by a dileucine motif on the cytoplasmic C-terminal domain of GluK3b in heterologous cells, in cultured hippocampal neurons, and in dentate granule cells from organotypic slice cultures. The internalization of GluK3b is clathrin and dynamin2 dependent. GluK3b is differentially endocytosed in dendrites as compared to the axons. These data suggest that the polarized trafficking of KARs in neurons could be controlled by the regulation of receptor endocytosis. |
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Hémar A, Mulle C.
Alzheimer's disease, amyloïd peptide and synaptic dysfunction. Med Sci (Paris). 2011 Aug-Sep;27(8-9):733-6. 2011
Liens vers résumé
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| Unité |
Institut Interdisciplinaire de Neurosciences - Daniel Choquet |
| Equipe |
Physiologie des synapses glutamatergiques - Christophe Mulle |
| Axe de recherche |
Synapse ; Neurobiologie du développement |
| Abstract |
Alzheimer's disease (AD) is the first cause of dementia that leads to insidious and progressive loss of memory and cognitive functions. In the early stages of AD, there is a strong correlation between memory impairment and cortical levels of soluble amyloid-ß peptide oligomers (Aß). It has become clear that Aß disrupt glutamatergic synaptic function, which in turn may lead to the characteristic cognitive deficits. Conversely, experiments in rodents have conforted the notion that Aßo impairs synaptic transmission and plasticity, and that mouse models with increased production of these oligomers display cognitive impairment. Many studies have attempted to determine the mechanisms by which Aßo disrupt synaptic plasticity and mediate their detrimental effect, but the actual pathways are still poorly understood. Here we review this thriving area of research which aims at undertanding the mechanisms of synaptic dysfunction in the early phase of AD, and its consequences on the activity of neural circuits. |
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