A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior

P De Rossi, E Harde, J P Dupuis, L Martin, N Chounlamountri, M Bardin, C Watrin, C Benetollo, K Pernet-Gallay, H J Luhmann, J Honnorat, G Malleret, L Groc, A Acker-Palmer, P A Salin, C Meissirel
Mol Psychiatry. 2016-01-05; 21(12): 1768-1780
DOI: 10.1038/mp.2015.195

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De Rossi P(1)(2)(3), Harde E(4)(5)(6), Dupuis JP(7)(8), Martin L(1)(2)(3),
Chounlamountri N(1)(2)(3), Bardin M(1)(2)(3), Watrin C(1)(2)(3), Benetollo
C(1)(2)(9), Pernet-Gallay K(10)(11), Luhmann HJ(12), Honnorat J(1)(2)(13),
Malleret G(1)(2)(14), Groc L(7)(8), Acker-Palmer A(4)(5)(6), Salin PA(1)(2)(14),
Meissirel C(1)(2)(3).

Author information:
(1)Institut National de la Santé et de la Recherche Médicale, Unité 1028, Centre
National de la Recherche Scientifique, Unité Mixte de Recherche 5292, Lyon,
(2)Claude Bernard University Lyon 1, Lyon, France.
(3)Neurooncology and Neuroinflammation, Lyon Neuroscience Research Center, Lyon,
(4)Institute of Cell Biology and Neuroscience and BMLS, Goethe University
Frankfurt, Frankfurt, Germany.
(5)Max Planck Institute for Brain Research, Frankfurt, Germany.
(6)Focus Program Translational Neurosciences, University of Mainz, Mainz,
(7)Interdisciplinary Institute for Neuroscience, Unité Mixte de Recherche 5297,
Université de Bordeaux, Bordeaux, France.
(8)Interdisciplinary Institute for Neuroscience, UMR 5297, Centre National de la
Recherche Scientifique, Bordeaux, France.
(9)Functional Neurogenomics and Optogenetics, Lyon Neuroscience Research Center,
Lyon, France.
(10)Grenoble Institute of Neurosciences, Grenoble, France.
(11)INSERM U836, Microscopy and Electron Microscopy Platform, Grenoble, France.
(12)Institute of Physiology, University Medical Center, University of Mainz,
Mainz, Germany.
(13)Neuro-Oncology Department, Hospices Civils de Lyon, Hôpital Neurologique,
Lyon, France.
(14)Forgetting and Cortical Dynamics, Lyon Neuroscience Research Center, Lyon,

Vascular endothelial growth factor (VEGF) is known to be required for the action
of antidepressant therapies but its impact on brain synaptic function is poorly
characterized. Using a combination of electrophysiological, single-molecule
imaging and conditional transgenic approaches, we identified the molecular basis
of the VEGF effect on synaptic transmission and plasticity. VEGF increases the
postsynaptic responses mediated by the N-methyl-D-aspartate type of glutamate
receptors (GluNRs) in hippocampal neurons. This is concurrent with the formation
of new synapses and with the synaptic recruitment of GluNR expressing the GluN2B
subunit (GluNR-2B). VEGF induces a rapid redistribution of GluNR-2B at synaptic
sites by increasing the surface dynamics of these receptors within the membrane.
Consistently, silencing the expression of the VEGF receptor 2 (VEGFR2) in neural
cells impairs hippocampal-dependent synaptic plasticity and consolidation of
emotional memory. These findings demonstrated the direct implication of VEGF
signaling in neurons via VEGFR2 in proper synaptic function. They highlight the
potential of VEGF as a key regulator of GluNR synaptic function and suggest a
role for VEGF in new therapeutic approaches targeting GluNR in depression.


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