Role of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine
| Autor: | Eunyoung Bang, Xiaoyuan Li, Seth R. Taylor, Sophie Dutheil, Satoshi Deyama, Taro Kato, Eric S. Wohleb, Danielle M. Gerhard, Ronald S. Duman, Jason M. Dwyer, Marina R. Picciotto |
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| Rok vydání: | 2019 |
| Předmět: |
Vascular Endothelial Growth Factor A
medicine.drug_class Prefrontal Cortex In Vitro Techniques Behavioral neuroscience Article Gene Knockout Techniques Mice 03 medical and health sciences 0302 clinical medicine medicine Animals VEGF signaling Ketamine Prefrontal cortex Depression (differential diagnoses) Neurons Behavior Animal business.industry medicine.disease Receptor antagonist Antibodies Neutralizing Vascular Endothelial Growth Factor Receptor-2 Antidepressive Agents 030227 psychiatry Psychiatry and Mental health nervous system Mood disorders Gene Knockdown Techniques Quinazolines Antidepressant business Excitatory Amino Acid Antagonists Neuroscience 030217 neurology & neurosurgery Signal Transduction medicine.drug |
| Zdroj: | Am J Psychiatry |
| ISSN: | 1535-7228 0002-953X |
| DOI: | 10.1176/appi.ajp.2018.17121368 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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