De Rossi P, Harde E, Dupuis J P, Martin L, Chounlamountri N, Bardin M, Watrin C, Benetollo C, Pernet-Gallay K, Luhmann H J, Honnorat J, Malleret G, Groc L, Acker-Palmer A, Salin P A, Meissirel C
Institut National de la Santé et de la Recherche Médicale, Unité 1028, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5292, Lyon, France.
Claude Bernard University Lyon 1, Lyon, France.
Mol Psychiatry. 2016 Dec;21(12):1768-1780. doi: 10.1038/mp.2015.195. Epub 2016 Jan 5.
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.
血管内皮生长因子（VEGF）已知是抗抑郁疗法发挥作用所必需的，但它对脑突触功能的影响却鲜有明确阐述。通过结合电生理学、单分子成像和条件转基因方法，我们确定了VEGF对突触传递和可塑性产生影响的分子基础。VEGF可增强海马神经元中由N-甲基-D-天冬氨酸型谷氨酸受体（GluNRs）介导的突触后反应。这与新突触的形成以及表达GluN2B亚基的GluNR（GluNR-2B）的突触募集同时发生。VEGF通过增加这些受体在膜内的表面动力学，诱导GluNR-2B在突触部位快速重新分布。同样，沉默神经细胞中血管内皮生长因子受体2（VEGFR2）的表达会损害海马依赖性突触可塑性和情绪记忆巩固。这些发现证明了VEGF信号通过VEGFR2在神经元中对正常突触功能的直接影响。它们突出了VEGF作为GluNR突触功能关键调节因子的潜力，并提示VEGF在针对抑郁症中GluNR的新治疗方法中发挥作用。
