Anxio-depressive phenotype and impaired memory in mice with a conditional knockout of brain-derived neurotrophic factor in endothelial cells.

Abstract

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 (BDNF^ECKO) 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. BDNF^ECKO mice exhibited anxio-depressive phenotype, impaired memory, and reduced synaptogenesis. Neither neuronal activity, neuronal BDNF/TrkB signaling, nor capillary density differed between BDNF^ECKO and WT mice. However, endothelial-activated TrkB receptors as well as endothelial NO production and hippocampal BDNF levels were lower in BDNF^ECKO 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.NEW & NOTEWORTHY 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.