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Séminaire - Pedro Grandes & Ana Gutierrez"New cellular mechanisms and anatomy of the endocannabinoid-dependent synaptic plasticity in the hippocampus"

Abstract :

Abstract

The endocannabinoid (eCB) system is a complex endogenous signalling system that participates in multiple metabolic pathways. It is composed of cannabinoid (CB) receptors, their endogenous ligands or endocannabinoids and the proteins involved in their synthesis, degradation and transport, as well as the intracellular signalling pathways regulated by eCBs. The CB1 receptor is highly expressed in the central nervous system, being the most abundant G-protein coupled receptor in the brain. Amongst many other physiological functions, the eCB system modulates synaptic transmission and plasticity in many brain structures through the activation of CB1. However, a deeper knowledge of the interactions between the eCB system with metabotropic glutamate (mGlu) receptors and the transient receptor potential vanilloid type-1 (TRPV1) is still needed for a better understanding of the eCB-mediated synaptic plasticity.
It´s well established that activation of postsynaptic group I mGlu1 and, particularly, mGlu5 receptors gives rise to the synthesis of endocannabinoids that activate presynaptic CB1. This triggers a long term depression (LTD) of the synaptic transmission. In addition, there are some pieces of evidence suggesting that the activation of postsynaptic group II mGlu receptors elicits LTD through the activity of phospholipase C. So, we asked whether group II mGlu receptors, particularly mGlu3 at postsynaptic sites of the hippocampal medial perforant path synapses, participates in an endocannabinoid-mediated LTD at these excitatory synapses. To this end, we applied electrophysiological and high resolution anatomical techniques to the hippocampus of wild-type and mutant mice. Our observations suggest that a postsynaptic activation of both mGlu3 and mGlu5 is needed for a full CB1-dependent LTD at the hippocampal medial perforant path synapses.
In the second part of the talk, compelling anatomical evidence on the subcellular compartmentalization of TRPV1 in the hippocampal dentate molecular layer will be shown. These results will hopefully give some light on the controversial and highly debated TRPV1 expression in the brain.

Selected publications

Le Meur, K., Mendizabal-Zubiaga, J., Grandes, P. y Audinat, E. GABA release by hippocampal astrocytes.Frontiers in Computational Neuroscience, 6 (59): 1-10 (2012)

Ramos-Uriarte, A., Elezgarai, I., Grandes, P. y Gómez-Urquijo, S.M. Conserved cellular distribution of the glutamate receptors GluA2/3, mGlu1a and mGlu2/3 in isolated cultures of rat cerebellum. Journal of Chemical Neuroanatomy, 45(1-2): 26-35 (2012)

Benard, 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, Ch. Ortega-Gutierrez, S., Martín-Fontecha, M., Klugmann, M., Guggenhuber, S., Lutz, B., Jürg Gertsch, J., Chaouloff1, F., López-Rodríguez, M.L., Grandes, P., Rossignol, R. y Marsicano, G. Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nature Neuroscience, 15 (4): 558-564 (2012)

Han, J., Kesner, Ph., Metna-Laurent, M., Duan, T., Xu, L., Georges, F., Koehl, M., Abrous, D.N., Mendizabal-Zubiaga, J., Grandes, P., Liu, Q., Bai, G., Wang, W., Xiong, L., Ren, W., Marsicano, G. y Zhang, X.Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell, 148: 1039-1050 (2012)

Puente, N., Cui, Y., Lassalle, O., Lafourcade, M., Georges, F., Venance, L., Grandes, P. y Manzoni, O.J. Polymodal activation of the endocannabinoid system in the extended amygdala. Nature Neuroscience, 14 (12): 1542-1547 (2011)

Giovanni Marsicano (giovanni.marsicano @ inserm.fr)

We attempt to better understand the interactions of the endocannabinoid (eCB) system with excitatory and inhibitory circuits recruited during high brain functions processing; and to gain knowledge about how the disruption of those circuits leads to brain disease.
In particular, our laboratory is devoted to:
• Investigate the cellular mechanisms involved in eCB-mediated synaptic plasticity.
• Determine the anatomical and functional interplays between the eCb system and classical membrane receptors at excitatory and inhibitory synapses.
• Elucidate the molecular organization of the components of the eCB system.
• Study the eCB system in animal models of stress.
To achieve these goals, we use an interdisciplinary strategy combining electrophysiological and anatomical techniques applied to brain tissue of wild-type and genetically modified mice. The methods currently used in the laboratory are:
- Immunocytochemistry for confocal microscopy and high resolution electron microscopy.
- Electrophysiology ex vivo in brain slices (extracellular field recordings and patch-clamp).
- Western blot and 2D proteomics.