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PNAS 108 (33): 13782-13787

Copyright © 2011 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / NEUROSCIENCE

VEGF modulates NMDA receptors activity in cerebellar granule cells through Src-family kinases before synapse formation

Claire Meissirela,b,1,2, Carmen Ruiz de Almodovarc,d,1, Ellen Knevelsc,d,1, Cathy Coulonc,d, Naura Chounlamountria,b, Inmaculada Segurac,d, Pierre de Rossia,b, Stefan Vinckierc,d, Kristof Anthonisc,d, Bérangère Deléglisea,b, Maria de Molc,d, Carine Alie,f,g, Karel Dassonvillea,b, Ellen Loyensh, Jérôme Honnorata,b, Yvette Michotteh, Véronique Rogemonda,b, Ilse Smoldersh, Thomas Voetsi, Denis Viviene,f,g, Pieter Vanden Berghej, Ludo Van Den Boschd,k, Wim Robberechtd,k,l, Alain Chédotalm, Salvatore Olivieron, Mieke Dewerchinc,d, Dietmar Schmuckerd,o, Nicole Thomasseta,b,1, Paul Salina,b,p,1, and Peter Carmelietc,d,1,2

aInstitut National de la Santé et de la Recherche Médicale (INSERM), Unité 1028, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5292, Neurooncology and Neuroinflammation, Lyon Neuroscience Research Center, F-69000 Lyon, France; b University Lyon 1, F-69000 Lyon, France; cLaboratory for Angiogenesis and Neurovascular Link, kLaboratory of Neurobiology, and oLaboratory of Neuronal Wiring, dVesalius Research Center, VIB, K.U. Leuven, B-3000 Leuven, Belgium; eINSERM, Unité 919, Serine Proteases and Pathophysiology of the Neurovascular Unit, and fCentre National de la Recherche Scientifique, Unité Mixte de Recherche 6232, Center for Imaging Neurosciences and Applications to Pathologies, Cyceron, F-14074 Caen Cedex, France; g University of Caen Basse-Normandie, F-14074 Caen Cedex, France; hDepartment of Pharmaceutical Chemistry, Drug Analysis, and Drug Information, Vrije Universiteit Brussel, 1090 Brussels, Belgium; iLaboratory of Ion Channel Research, and jCenter for Gastroenterological Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; lDepartment of Neurology, University Hospital Leuven, B-3000 Leuven, Belgium; mINSERM, Unité Mixte de Recherche S968, Department of Development, Institute of Vision, F-75012 Paris, France; nDepartment of Molecular Biology, Università di Siena, 53100 Siena, Italy; and pINSERM Unité 1028, Centre National de la Reserche Scientifique Unité Mixte de Reserche 5292, Physiopathology of the Sleep Neuronal Networks, Lyon Neuroscience Research Center, F-69000 Lyon, France

Edited* by Don W. Cleveland, University of California at San Diego, La Jolla, CA, and approved July 7, 2011 (received for review January 15, 2011)

Abstract: NMDA type glutamate receptors (NMDARs) are best known for their role in synaptogenesis and synaptic plasticity. Much less is known about their developmental role before neurons form synapses. We report here that VEGF, which promotes migration of granule cells (GCs) during postnatal cerebellar development, enhances NMDAR-mediated currents and Ca2+ influx in immature GCs before synapse formation. The VEGF receptor Flk1 forms a complex with the NMDAR subunits NR1 and NR2B. In response to VEGF, the number of Flk1/NR2B coclusters on the cell surface increases. Stimulation of Flk1 by VEGF activates Src-family kinases, which increases tyrosine phosphorylation of NR2B. Inhibition of Src-family kinases abolishes the VEGF-dependent NR2B phosphorylation and amplification of NMDAR-mediated currents and Ca2+ influx in GCs. These findings identify VEGF as a modulator of NMDARs before synapse formation and highlight a link between an activity-independent neurovascular guidance cue (VEGF) and an activity-regulated neurotransmitter receptor (NMDAR).

Key Words: angiogenesis • neurovascular link • neuronal migration • cerebellum

Author contributions: C.M., C.R.d.A., E.K., C.C., I. Segura, S.V., M.d.M., C.A., J.H., I. Smolders, T.V., D.V., P.V.B., L.V.D.B., W.R., A.C., M.D., D.S., N.T., P.S., and P.C. designed research; C.M., C.R.d.A., E.K., C.C., N.C., I. Segura, P.d.R., S.V., K.A., B.D., M.d.M., K.D., E.L., Y.M., V.R., P.V.B., and P.S. performed research; J.H., I. Smolders, S.O., D.S., and N.T. contributed new reagents/analytic tools; C.M., C.R.d.A., E.K., C.C., C.A., T.V., D.V., P.V.B., L.V.D.B., W.R., A.C., M.D., D.S., N.T., and P.S. analyzed data; and C.M., C.R.d.A., P.S., and P.C. wrote the paper.

1C.M., C.R.d.A., E.K., N.T., P.S., and P.C. contributed equally to the work.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1100341108/-/DCSupplemental.

2To whom correspondence may be addressed. E-mail: claire.meissirel{at}inserm.fr or peter.carmeliet{at}vib-kuleuven.be.

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