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Role of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine

American Journal of Psychiatry, 2019-05, Vol.176 (5), p.388-400 [Peer Reviewed Journal]

Copyright © 2019 by the American Psychiatric Association ;Copyright American Psychiatric Association May 1, 2019 ;ISSN: 0002-953X ;EISSN: 1535-7228 ;DOI: 10.1176/appi.ajp.2018.17121368 ;PMID: 30606046

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Title:
Role of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine
Author: Deyama, Satoshi ; Bang, Eunyoung ; Wohleb, Eric S ; Li, Xiao-Yuan ; Kato, Taro ; Gerhard, Danielle M ; Dutheil, Sophie ; Dwyer, Jason M ; Taylor, Seth R ; Picciotto, Marina R ; Duman, Ronald S
Subjects: Animals ; Antibodies, Neutralizing - pharmacology ; Antidepressants ; Behavior, Animal - drug effects ; Excitatory Amino Acid Antagonists - pharmacology ; Gene Knockdown Techniques ; Gene Knockout Techniques ; In Vitro Techniques ; Ketamine - pharmacology ; Mice ; Neurons ; Neurons - drug effects ; Neurons - metabolism ; Neurons - pathology ; Prefrontal Cortex - drug effects ; Prefrontal Cortex - metabolism ; Quinazolines - pharmacology ; Signal Transduction ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - drug effects ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism ; Vascular Endothelial Growth Factor Receptor-2 - drug effects ; Vascular Endothelial Growth Factor Receptor-2 - genetics ; Vascular Endothelial Growth Factor Receptor-2 - metabolism
Is Part Of: American Journal of Psychiatry, 2019-05, Vol.176 (5), p.388-400
Description: Objective:The N-methyl-d-aspartate receptor antagonist ketamine produces rapid and sustained antidepressant actions even in patients with treatment-resistant depression. 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. The authors examined whether neuronal VEGF signaling in the medial prefrontal cortex (mPFC) mediates the rapid antidepressant actions of ketamine.Methods:The authors 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 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.
Publisher: United States: American Psychiatric Association
Language: English
Identifier: ISSN: 0002-953X
EISSN: 1535-7228
DOI: 10.1176/appi.ajp.2018.17121368
PMID: 30606046
Source: MEDLINE
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Role of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine

Copyright © 2019 by the American Psychiatric Association ;Copyright American Psychiatric Association May 1, 2019 ;ISSN: 0002-953X ;EISSN: 1535-7228 ;DOI: 10.1176/appi.ajp.2018.17121368 ;PMID: 30606046

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