Quirié Aurore, Mor Damien, Méloux Alexandre, Etievant Adeline, Garnier Philippe, Totoson Perle, Wirtz Julien, Prigent-Tessier Anne, Marie Christine, Demougeot Céline
INSERM UMR1093-CAPS, Université de Bourgogne, UFR Sciences de Santé, Dijon, France.
UMR INSERM 1322 LINC, Université de Franche-Comté, Besançon, France.
Am J Physiol Cell Physiol. 2025 Jan 1;328(1):C303-C314. doi: 10.1152/ajpcell.00699.2024. Epub 2024 Dec 9.
The present study investigated the role of endothelial brain-derived neurotrophic factor (BDNF) in cognition. Male adult mice with a selective knockout of BDNF in endothelial cells () and their wild-type (WT) littermates were subjected to tests for detection of anxiety- and depression-like behaviors and impaired recognition memory. Neuronal activity and synaptogenesis were assessed from hippocampal levels of c-fos and synaptophysin, respectively, and cerebral capillary density from forebrain levels of CD31. BDNF/TrkB (tropomyosin-related kinase type B) receptor signaling was investigated through hippocampal levels of BDNF and activated TrkB receptors coupled with their immunolabeling by neurons and endothelial cells from both cerebrovascular fractions enriched in capillaries and hippocampal arterioles. Endothelial nitric oxide (NO) production was assessed from the expression of endothelial NO synthase phosphorylated at serine 1177. mice exhibited anxio-depressive phenotype, impaired memory, and reduced synaptogenesis. Neither neuronal activity, neuronal BDNF/TrkB signaling, nor capillary density differed between and WT mice. However, endothelial-activated TrkB receptors as well as endothelial NO production and hippocampal BDNF levels were lower in than those in WT mice. We conclude that endothelial BDNF is involved in cognition through mechanisms independent of neuronal BDNF/TrkB signaling and that endothelial NO might be a driver of the procognitive effect of endothelial BDNF. The study provides the proof of concept that endothelial brain-derived neurotrophic factor (BDNF) plays a crucial role in postnatal synaptogenesis and development of behavior/memory. It also shows that neuronal tropomyosin-related kinase type B (TrkB) receptors are not a target of endothelium-derived BDNF.
本研究调查了内皮源性脑源性神经营养因子（BDNF）在认知中的作用。对在内皮细胞中选择性敲除BDNF的成年雄性小鼠（ ）及其野生型（WT）同窝小鼠进行了焦虑样和抑郁样行为检测以及识别记忆受损测试。分别从海马体中c-fos水平和突触素水平评估神经元活性和突触形成，从前脑CD31水平评估脑毛细血管密度。通过海马体中BDNF水平和活化的TrkB受体以及它们在富含毛细血管的脑血管部分和海马小动脉的神经元和内皮细胞的免疫标记来研究BDNF/TrkB（原肌球蛋白相关激酶B型）受体信号传导。从丝氨酸1177位点磷酸化的内皮型一氧化氮合酶的表达评估内皮一氧化氮（NO）的产生。 小鼠表现出焦虑抑郁表型、记忆受损和突触形成减少。 小鼠和WT小鼠之间的神经元活性、神经元BDNF/TrkB信号传导或毛细血管密度均无差异。然而， 小鼠中内皮活化的TrkB受体以及内皮NO产生和海马体BDNF水平均低于WT小鼠。我们得出结论，内皮BDNF通过独立于神经元BDNF/TrkB信号传导的机制参与认知，并且内皮NO可能是内皮BDNF促认知作用的驱动因素。该研究提供了概念证明，即内皮源性脑源性神经营养因子（BDNF）在出生后突触形成以及行为/记忆发展中起关键作用。它还表明神经元原肌球蛋白相关激酶B型（TrkB）受体不是内皮源性BDNF的靶点。
