Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
Biol Psychiatry. 2019 Jul 15;86(2):143-152. doi: 10.1016/j.biopsych.2018.12.014. Epub 2018 Dec 27.
Activity-dependent release of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) is essential for the rapid and sustained antidepressant actions of ketamine, and a recent study shows a similar requirement for vascular endothelial growth factor (VEGF). Since BDNF is reported to stimulate VEGF expression and/or release in neuroblastoma cells, the present study tested the hypothesis that the actions of BDNF are mediated by VEGF.
The role of VEGF in the antidepressant behavioral actions of BDNF was tested by intra-mPFC coinfusion of a VEGF neutralizing antibody and by neuron-specific deletion of VEGF. The influence of BDNF on the release of VEGF and the role of VEGF in the neurotrophic actions of BDNF were determined in rat primary cortical neurons. The role of BDNF in the behavioral and neurotrophic actions of VEGF was also determined.
The results show that the rapid and sustained antidepressant-like actions of intra-mPFC BDNF are blocked by coinfusion of a VEGF neutralizing antibody, and that neuron-specific mPFC deletion of VEGF blocks the antidepressant-like actions of BDNF. Studies in primary cortical neurons demonstrate that BDNF stimulates the release of VEGF and that BDNF induction of dendrite complexity is blocked by a selective VEGF-fetal liver kinase 1 receptor antagonist. Surprisingly, the results also show reciprocal interactions, indicating that the behavioral and neurotrophic actions of VEGF are dependent on BDNF.
These findings indicate that the antidepressant-like and neurotrophic actions of BDNF require VEGF signaling, but they also demonstrate reciprocal interdependence for BDNF in the actions of VEGF.
脑源性神经营养因子（BDNF）在额前皮质（mPFC）中的活性依赖性释放对于氯胺酮的快速和持续抗抑郁作用至关重要，最近的一项研究表明血管内皮生长因子（VEGF）也有类似的要求。由于据报道 BDNF 可刺激神经母细胞瘤细胞中 VEGF 的表达和/或释放，因此本研究检验了 BDNF 作用是通过 VEGF 介导的假设。
通过在 mPFC 中共输注 VEGF 中和抗体和神经元特异性缺失 VEGF 来测试 VEGF 在 BDNF 抗抑郁行为作用中的作用。在大鼠原代皮质神经元中确定 BDNF 对 VEGF 释放的影响以及 VEGF 在 BDNF 神经营养作用中的作用。还确定了 BDNF 在 VEGF 的行为和神经营养作用中的作用。
结果表明，mPFC 中 BDNF 的快速和持续抗抑郁样作用被共输注 VEGF 中和抗体所阻断，神经元特异性 mPFC 中 VEGF 的缺失阻断了 BDNF 的抗抑郁样作用。原代皮质神经元研究表明，BDNF 刺激 VEGF 的释放，而 BDNF 诱导树突复杂性的作用被选择性 VEGF-胎肝激酶 1 受体拮抗剂阻断。令人惊讶的是，结果还显示出相互作用，表明 VEGF 的行为和神经营养作用依赖于 BDNF。
这些发现表明，BDNF 的抗抑郁样和神经营养作用需要 VEGF 信号，但它们也证明了 VEGF 作用中 BDNF 的相互依存关系。
