The neurotrophic and antidepressant actions of BDNF and VEGF require interactive signaling

Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in the medial prefrontal cortex (mPFC) work together to produce antidepressant effects. In cultured cortical neurons, BDNF stimulates VEGF release and VEGF stimulates BDNF release. BDNF increases dendritic complexity, but this effect is blocked by inhibiting the VEGF receptor Flk-1; similarly, VEGF's effect on dendrites is blocked by inhibiting the BDNF receptor TrkB. A single infusion of either BDNF or VEGF into the mPFC of mice produces antidepressant effects lasting at least 5 days in three behavioral tests. These effects are blocked by neutralizing the other factor, indicating that mutual signaling between BDNF and VEGF is required for rapid and sustained antidepressant responses.

Study at a glance

Abstract

Previous studies have shown that activity-dependent release of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) is required for the antidepressant actions of ketamine. Recently, we have found that neuronal vascular endothelial growth factor (VEGF),signaling in the mPFC also plays a crucial role in the antidepressant actions of this rapid acting agent. However, it remains unclear whether these growth factors act in series or parallel, and the current study examines the interplay between BDNF and VEGF signaling in the neurotrophic and antidepressant actions of these pleiotrophic factors. We demonstrate that BDNF and VEGF stimulate heterologous release of the other factor in primary cultured cortical neurons. In addition, BDNF significantly increases dendritic complexity of primary cortical neurons, and this effect is blocked by incubation with an inhibitor of a primary VEGF receptor, Flk-1/VEGF-R2. VEGF also increases dendritic complexity, and this effect is completely blocked by incubation with an inhibitor of the primary BDNF receptor, TrkB. These results indicate that neurotrophic responses require heterologous BDNF-TrkB and VEGF-Flk-1 signaling. Next, we examined whether BDNF or VEGF signaling in the mPFC is sufficient to produce antidepressant effects in three different models, the forced swim test, female urine sniffing test, and novelty-suppressed feeding test. The results demonstrate that a single intra-mPFC infusion of either BDNF or VEGF produces antidepressant effects in all three tests, and these effects are maintained for at least 5 days after the infusions. Importantly, we found that the antidepressant effects of intra-mPFC VEGF infusion are blocked by co-infusion of a BDNF neutralizing antibody, and conversely, that the antidepressant effects of intra-mPFC BDNF infusion are blocked by co-infusion of VEGF neutralizing antibody or by neuron-specific deletion of VEGF (CaMKII-Cre x VEGFflox/flox mice). Together, the current results indicate that a heterologous interplay between BDNF and VEGF signaling in the mPFC is required to produce rapid and sustained antidepressant responses to these neurotrophic factors.