PhD: Sabine Fievre

Molecular mechanisms for synaptic stabilization of kainate receptors in CA3 pyramidal cells

November 19th, 2015

Team Christophe Mulle – “Physiology of Glutamatergic Synapses” de l’Institut IINS 

Doctorante ayant bénéficié d’une bourse de soudure LabEx BRAIN.

Molecular mechanisms for synaptic stabilization of kainate receptors in CA3 pyramidal cells

Distinct subtypes of ionotropic glutamate receptors can be segregate to specific synaptic inputs in a given neuron. In CA3 pyramidal cells (PCs), kainate receptors (KARs) are present at mossy fiber (mf) synapses and absent from other glutamatergic inputs. The mechanisms for such a constrained subcellular segregation is not known.

We have investigated the molecular determinants responsible for the subcellular segregation of KARs at mf-CA3 synapses. Using functional mapping of glutamate receptors by focal glutamate uncaging we show that KARs display a strictly confined expression on thorny excrescences, the postsynaptic elements of mf-CA3 synapses, being excluded from extrasynaptic somatodendritic compartments, at variance with AMPA receptors.

We have identified a sequence in the GluK2a C-terminal domain necessary for restricted expression of KARs which is responsible for GluK2a interaction with N-Cadherin. Targeted deletion of N-Cadherin or overexpression of a dominant negative N-Cadherin in CA3 PCs greatly induce a destabilization of KARs at the mf-CA3 synapses. Our findings suggest that multiple mechanisms combine to control the compartimentalization of KARs at mf-CA3 synapses, including a stringent control of the amount of GluK2 subunit in CA3 PCs, a limited number of slots for KARs, and the recruitment/stabilization of KARs by N-Cadherins.

Key words: Synapse specification – subcellular segregation – kainate receptor – CA3 – N-Cadherin


Publications :

Piguel, N. H., Fievre, S., Blanc, J.-M., Carta, M., Moreau, M. M., Moutin, E., et al. (2014). Scribble1/AP2 Complex Coordinates NMDA Receptor Endocytic Recycling. Cell Reports, 1–17. doi:10.1016/j.celrep.2014.09.017

Carta, M., Fievre, S., Gorlewicz, A., & Mulle, C. (2014). Kainate receptors in the hippocampus. The European Journal of Neuroscience, 39(11), 1835–1844. doi:10.1111/ejn.12590

Fievre, S., Carta, M., Labrousse, V., Mulle, C. Molecular determinant for the stricly compartmentalized expression of kainate receptors in CA3 pyramidal cells. Soumis

Jury

Président 
Olivier Thoumine, IINS
Directeur de thèse
Christophe Mulle, DR, IINS
Rapporteur 
Valérie Crepel
DR, Institut de Neurobiologie de la Méditerranée 

Rapporteur  
Stéphane Martin
DR, Institut de Pharmacologie Moléculaire et Cellulaire, Nice 

Examinateur
Geoffrey Swanson
DR, Northwestern University Feinberg School of Medecine, Chicago, USA

(Conférence Geoffrey Swanson le 20 Nov 11h30 )

Directeur de thèse

Christophe Mulle
Research Director

CNRS UMR 5297
Interdisciplinary Institute of Neuroscience
University of Bordeaux
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Last update: 9 April 2018