Neuron-specific deletion of VEGF or its receptor Flk-1 impairs recognition memory

Vascular endothelial growth factor (VEGF, also known as VEGF-A) is a pleiotropic factor which is expressed by neurons, astrocytes and perivascular macrophages, as well as endothelial cells, in the brain. Recently, VEGF signaling has been implicated in learning and memory, and several clinical and preclinical studies demonstrate that VEGF inhibitors induce cognitive impairment. However, the role of endogenous neuronal VEGF signaling in recognition memory remains unclear. Recently, we have developed mice with forebrain excitatory neuron-specific deletion of VEGF or its receptor, fetal liver kinase 1 (Flk-1) by crossing Camk2a-Cre mice with Vegfa^flox/flox and Flk-1^flox/flox mice, respectively. Using these conditional knockout mice, the present study addressed the influence of forebrain excitatory neuron-specific deletion of VEGF or Flk-1 on recognition memory in the novel object recognition test. The results show that both short-term (2 h) and long-term (24 h) recognition memory are impaired by neuron-specific deletion of either Flk-1 or VEGF. These findings indicate the physiological importance of endogenous neuronal VEGF-Flk-1 signaling in recognition memory. In addition, the current results also suggest that the impairment of neuronal VEGF-Flk-1 signaling can be a cause of anti-VEGF chemotherapy-induced cognitive impairment.