Seminar – Marina CEFIS

Brain-derived neurotrophic factor (BDNF) is a key regulator of synaptic plasticity, neuronal survival, and cognitive function, exerting its effects primarily through its high-affinity receptor TrkB. While research has traditionally focused on neurons as the main source of BDNF in the brain, endothelial cells also produce and release BDNF. However, the specific role of endothelial-derived BDNF in neuroplasticity and cognitive function has remained largely unexplored.

To address this question, we used a mouse model with a conditional, endothelial cell-specific knockout of BDNF (BDNF^ECKO). In a recently published study from our laboratory (Quirié et al., 2025), BDNF^ECKO mice and their wild-type (WT) littermates were subjected to behavioral tests assessing anxiety- and depression-like behaviors and memory, alongside molecular analyses including hippocampal BDNF levels, neuronal activity (c-fos), synaptogenesis (synaptophysin), cerebral capillary density (CD31), cell-specific TrkB receptor activation, and endothelial Nitric oxide (NO) production (p-eNOS^Ser1177).

BDNF^ECKO mice exhibited an anxio-depressive phenotype, impaired recognition memory, and reduced synaptogenesis. Although hippocampal BDNF levels were reduced, neither neuronal activity, neuronal TrkB receptor activation, nor cerebral capillary density differed from WT animals – excluding a neuronal BDNF/TrkB signaling contribution or cerebrovascular remodeling to the observed phenotype. In contrast, endothelial TrkB receptor activation and p-eNOS^Ser1177 expression were both significantly reduced, suggesting that endothelial NO may represent a key downstream effector of the pro-cognitive effects of endothelial BDNF.

Physical exercise is one of the most potent non-pharmacological stimuli known to elevate BDNF levels and promote neuroplasticity. Building on these findings, recent and unpublished behavioral and biochemical data from our laboratory examining the response of BDNF^ECKO mice to physical exercise will be presented. Physical exercise fully rescued spatial learning and memory in BDNF^ECKO mice, while affective-like behaviors were only partially restored in exercised BDNF^ECKO compared to WT. Strikingly, despite persistently reduced hippocampal BDNF levels in exercised BDNF^ECKO mice, the expression of neuroplastic proteins was markedly restored, suggesting that exercise recruits compensatory pathways to drive neuroplasticity at the synaptic level – opening new perspectives on the contribution of endothelial BDNF to exercise-induced brain adaptation at the neurovascular interface.