title: VEGF modulates NMDA receptors activity in cerebellar granule cells through Src-family kinases before synapse formation.
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 Ca(2+) 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 Ca(2+) 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).
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5292, Neurooncology and Neuroinflammation, Lyon Neuroscience Research Center, F-69000 Lyon, France. claire.meissirel@inserm.fr
authors.forename: Claire
authors.initials: C
authors.lastname: Meissirel
authors.forename: Carmen
authors.initials: C
authors.lastname: Ruiz de Almodovar
authors.forename: Ellen
authors.initials: E
authors.lastname: Knevels
authors.forename: Cathy
authors.initials: C
authors.lastname: Coulon
authors.forename: Naura
authors.initials: N
authors.lastname: Chounlamountri
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Segura
authors.forename: Pierre
authors.initials: P
authors.lastname: de Rossi
authors.forename: Stefan
authors.initials: S
authors.lastname: Vinckier
authors.forename: Kristof
authors.initials: K
authors.lastname: Anthonis
authors.forename: Bérangère
authors.initials: B
authors.lastname: Deléglise
authors.forename: Maria
authors.initials: M
authors.lastname: de Mol
authors.forename: Carine
authors.initials: C
authors.lastname: Ali
authors.forename: Karel
authors.initials: K
authors.lastname: Dassonville
authors.forename: Ellen
authors.initials: E
authors.lastname: Loyens
authors.forename: Jérôme
authors.initials: J
authors.lastname: Honnorat
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
authors.forename: Véronique
authors.initials: V
authors.lastname: Rogemond
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.forename: Pieter
authors.initials: P
authors.lastname: Vanden Berghe
authors.forename: Ludo
authors.initials: L
authors.lastname: Van den Bosch
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Alain
authors.initials: A
authors.lastname: Chédotal
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oliviero
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schmucker
authors.forename: Nicole
authors.initials: N
authors.lastname: Thomasset
authors.forename: Paul
authors.initials: P
authors.lastname: Salin
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D043925:Angiogenesis Inducing Agents; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology*; D051379:Mice; D046912:Multiprotein Complexes; D009474:Neurons / Q000648:ultrastructure*; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D017981:Receptors, Neurotransmitter; D013569:Synapses; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D043925:Angiogenesis Inducing Agents; D046912:Multiprotein Complexes; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases; D002118:Calcium