Deparment of Developmental Biology and Cancer Research, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel.
Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5081-6. doi: 10.1073/pnas.1007640108. Epub 2011 Mar 8.
Neurons, astrocytes, and blood vessels are organized in functional "neurovascular units" in which the vasculature can impact neuronal activity and, in turn, dynamically adjust to its change. Here we explored different mechanisms by which VEGF, a pleiotropic factor known to possess multiple activities vis-à-vis blood vessels and neurons, may affect adult neurogenesis and cognition. Conditional transgenic systems were used to reversibly overexpress VEGF or block endogenous VEGF in the hippocampus of adult mice. Importantly, this was done in settings that allowed the uncoupling of VEGF-promoted angiogenesis, neurogenesis, and memory. VEGF overexpression was found to augment all three processes, whereas VEGF blockade impaired memory without reducing hippocampal perfusion or neurogenesis. Pertinent to the general debate regarding the relative contribution of adult neurogenesis to memory, we found that memory gain by VEGF overexpression and memory impairment by VEGF blockade were already evident at early time points at which newly added neurons could not yet have become functional. Surprisingly, VEGF induction markedly increased in vivo long-term potentiation (LTP) responses in the dentate gyrus, and VEGF blockade completely abrogated LTP. Switching off ectopic VEGF production resulted in a return to a normal memory and LTP, indicating that ongoing VEGF is required to maintain increased plasticity. In summary, the study not only uncovered a surprising role for VEGF in neuronal plasticity, but also suggests that improved memory by VEGF is primarily a result of increasing plasticity of mature neurons rather than the contribution of newly added hippocampal neurons.
神经元、星形胶质细胞和血管组织在功能上形成“神经血管单元”，其中血管可以影响神经元活动，反过来，神经元活动也可以动态调节血管。在这里，我们探索了血管内皮生长因子（VEGF）的多种作用机制，VEGF 是一种多效因子，已知对血管和神经元具有多种作用，它可能影响成年神经发生和认知。使用条件性转基因系统可在成年小鼠海马体中可逆地过表达 VEGF 或阻断内源性 VEGF。重要的是，这是在可以分离 VEGF 促进血管生成、神经发生和记忆的情况下完成的。结果发现，VEGF 过表达会增强这三个过程，而 VEGF 阻断则会损害记忆，而不会减少海马灌注或神经发生。与关于成年神经发生对记忆的相对贡献的普遍争论有关，我们发现，VEGF 过表达引起的记忆增强和 VEGF 阻断引起的记忆障碍，在新增加的神经元还没有变得有功能的早期时间点就已经明显。令人惊讶的是，VEGF 诱导显著增加了齿状回中的体内长时程增强（LTP）反应，而 VEGF 阻断完全消除了 LTP。关闭异位 VEGF 产生导致记忆和 LTP 恢复正常，表明持续的 VEGF 是维持增加的可塑性所必需的。总之，该研究不仅揭示了 VEGF 在神经元可塑性中的惊人作用，还表明 VEGF 通过提高记忆主要是通过增加成熟神经元的可塑性，而不是新增加的海马神经元的贡献。
