English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Major depressive disorder causes a staggering burden worldwide (1). Because many first-line treatments are not efficacious, the psychiatric community continues to push for alternate pharmacological interventions, particularly for those suffering from treatment-resistant depression (2). Ketamine has gained attention as an alternative to typical antidepressants, as the induction of its antidepressant effects occurs within hours, as opposed to over the course of several weeks (3). While our understanding of the precise mechanisms that mediate the effects of ketamine has remained elusive, several preclinical studies suggest that ketamine affects synaptic plasticity in the medial prefrontal cortex (mPFC) and hippocampus via several cell signaling pathways (4). Although research in clinical populations is essential for moving forward with ketamine and other fast-acting antidepressants, animalmodels canhelpbridge the gapbetween behavioral manifestations and the neural mechanisms that underlie responses to these drugs. Such research has been facilitated by developments over the last decade that have allowed researchers to manipulate neural circuits and the genes that regulate these circuits. It is important to note that ketamine, while effective in rapidly reducing depressive symptoms, is a drug that is subject to abuse and has significant side effects, raising concerns about its widespread clinical utility. Gaining insight into the mechanisms underlying ketamine’s antidepressant effects paves the way for developing new rapid-acting antidepressants without the dissociative effects and abuse potential of ketamine. In this regard, understanding the contribution of the many signaling systems that have been implicated in the mechanism of action of ketamine, including the N-methyl-D-aspartate (NMDA) receptor (5), the AMPA receptor (6), the glutamatergic system (4), and the opiate system (7), is essential. Consistent with the conception of major depressive disorder as a disorder of neuroplasticity (8), the function of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), has also been linked to ketamine response (9) and independently to major depression (4). A new article in this issue of the Journal by Deyama et al. (10) provides convincing evidence using myriad research methods in rodents to support the involvement of another neurotrophic factor, vascular endothelial growth factor (VEGF),whichsignals via its receptor, fetal liverkinase 1 (Flk-1), to mediate the effects seen following ketamine administration in a preclinical model of behavioral responses associated with depressive symptoms. Deyama et al. use a series of complementary molecular and behavioral methods to demonstrate that VEGF–Flk-1 signaling is involved in the mechanisms underlying the rapid antidepressant effects of ketamine. The authors genetically engineered mice to produce a neuron-specific deletion of VEGF or Flk-1 in the pyramidal cells of the mPFC and hippocampus. This conditional knockout of VEGF or Flk-1 blocked the acute effects of ketamine as assessed using behavioral paradigms thought to reflect constructs associated with depression. By blocking the availability of VEGF in the mPFC with a specific antibody, the authors also showed that the behavioral and neural effects of ketamine are related to the synaptic release of VEGF. In addition, VEGF infused into the mPFC resulted in ketamine-like behavioral effects. The authors confirmed involvement of VEGF–Flk-1 signaling using a different method to knock down the expression of Flk-1 in mPFC neurons. Similar to the conditional knockout, this short hairpin RNA-mediated knockdown blocked the behavioral effects of ketamine administration. Importantly, in the absence of stressful challenges, these molecular manipulations did not affect baseline behaviors. Together, these results indicate that VEGF–Flk-1 signaling in the mPFC is both necessary and sufficient for the acute behavioral actions of ketamine. To understand how VEGF–Flk-1 signaling mediates antidepressant-like effects, the authors explored processes related to neuroplasticity. Using neuronal cultures, the authors found that applicationof ketamineorVEGF increaseddendritic branching, an effect that was blocked by an Flk-1 inhibitor. In control mice, an injection of ketamine significantly increased synaptic density in mPFC pyramidal neurons, an effect that did not occur in the VEGF knockout mice. Together, these findings indicate that the antidepressant effects of ketamine, thought to involve the induction of neuroplasticity, are in part mediated by VEGF–Flk-1 signaling in the mPFC. Understanding at a subcellular level how these ligands and their receptor systems interact ... will contribute to the identification of additional novel treatment strategies.

New Insights Into the Mechanisms of Ketamine’s Antidepressant Effects: Understanding the Role of VEGF in Mediating Plasticity Processes