Dynamic remodeling of scaffold interactions in dendritic spines controls synaptic excitability
Enora Moutin1,2,3,4,
Fabrice Raynaud1,2,3,4,
Jonathan Roger1,2,3,4,
Emilie Pellegrino1,2,3,4,
Vincent Homburger1,2,3,4,
Federica Bertaso1,2,3,4,
Vincent Ollendorff5,
Joël Bockaert1,2,3,4,
Laurent Fagni1,2,3,4, , and
Julie Perroy1,2,3,4
1 Centre national de la recherche scientifique, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, Cedex 16, France
2 Institut National de la Santé et de la Recherche Médicale, U661, F-34000 Montpellier, Cedex 13, France
3 Université de Montpellier 1, UMR-5203, 34967 Montpellier, Cedex 02, France
4 Université de Montpellier 2, 34095 Montpellier, Cedex 05, France
5 UMR866 Dynamique Musculaire et Métabolisme, Institut National de la Recherche Agronomique, 34060 Montpellier, Cedex 01, France
Correspondence to Julie Perroy: julie.perroy{at}igf.cnrs.fr
Abstract:
Scaffolding proteins interact with membrane receptors to control signaling pathways and cellular functions. However, the dynamics and specific roles of interactions between different components of scaffold complexes are poorly understood because of the dearth of methods available to monitor binding interactions. Using a unique combination of single-cell bioluminescence resonance energy transfer imaging in living neurons and electrophysiological recordings, in this paper, we depict the role of glutamate receptor scaffold complex remodeling in space and time to control synaptic transmission. Despite a broad colocalization of the proteins in neurons, we show that spine-confined assembly/disassembly of this scaffold complex, physiologically triggered by sustained activation of synaptic NMDA (N-methyl-D-aspartate) receptors, induces physical association between ionotropic (NMDA) and metabotropic (mGlu5a) synaptic glutamate receptors. This physical interaction results in an mGlu5a receptor–mediated inhibition of NMDA currents, providing an activity-dependent negative feedback loop on NMDA receptor activity. Such protein scaffold remodeling represents a form of homeostatic control of synaptic excitability.
Abbreviations: BRET, bioluminescence resonance energy transfer • DHPG, dihydroxyphenylglycine • GKAP, guanylate kinase–associated protein • LTP, long-term potentiation • mEPSC, miniature excitatory postsynaptic current • NTA, nitrilotriacetic acid • shRNA, short hairpin RNA
