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OBJECTIVE: The NMDA receptor antagonist ketamine produces rapid and sustained antidepressant actions even in treatment-resistant depressed patients. Vascular endothelial growth factor (VEGF) has been implicated in the effects of conventional monoamine-based antidepressants, but the role of VEGF in the rapid antidepressant actions of ketamine remains unclear. Here, we examined whether neuronal VEGF signaling in the medial prefrontal cortex (mPFC) mediates the rapid antidepressant actions of ketamine. METHOD: For these studies we used a combination of approaches, including conditional, neuron-specific knockout of VEGF or its receptor Flk-1, antibody neutralization, viral-mediated knockdown of Flk-1, and pharmacological inhibitors. Further in vitro and in vivo experiments were performed to examine whether neuronal VEGF signaling was required for the neurotrophic and synaptogenic actions of ketamine that underlie its behavioral actions. RESULTS: The results demonstrate that the behavioral actions of systemic ketamine are blocked by forebrain excitatory neuron-specific deletion of either VEGF or Flk-1, or by intra-mPFC infusion of a VEGF neutralizing antibody. Moreover, intra-mPFC infusions of VEGF are sufficient to produce rapid ketamine-like behavioral actions, and these effects are blocked by neuron-specific Flk-1 deletion. The results also show that local knockdown of Flk-1 in mPFC excitatory neurons in adulthood blocks the behavioral effects of systemic ketamine. Moreover, inhibition of neuronal VEGF signaling blocks the neurotrophic and synaptogenic effects of ketamine. CONCLUSIONS: Together, these findings indicate that neuronal VEGF-Flk-1 signaling in the mPFC plays an essential role in the antidepressant actions of ketamine.