A metabolite of ketamine, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], produces rapid and sustained antidepressant effects in animal models without the side effects of ketamine and without blocking the NMDA receptor. The antidepressant effects require activity-dependent release of BDNF, mediated by stimulation of voltage-dependent Ca2+ channels. Increased BDNF release activates downstream TrkB and mechanistic target of rapamycin complex 1 signaling, which increases synaptic function of pyramidal neurons in the medial prefrontal cortex. Stimulation of BDNF release and increased synaptic function block or reverse the detrimental effects of stress and depression.
The antidepressant effects of ketamine require vascular endothelial growth factor (VEGF) signaling through its receptor Flk-1 in excitatory neurons of the medial prefrontal cortex (mPFC). Deleting VEGF or Flk-1 from forebrain excitatory neurons, or blocking VEGF in the mPFC, prevented ketamine's behavioral effects in mice. Infusing VEGF directly into the mPFC produced rapid antidepressant-like actions similar to ketamine, but these were blocked by Flk-1 deletion. Local knockdown of Flk-1 in adult mPFC excitatory neurons also blocked ketamine's effects. Additionally, blocking neuronal VEGF signaling prevented the neurotrophic and synaptogenic actions of ketamine. Neuronal VEGF-Flk-1 signaling in the mPFC is essential for ketamine's rapid antidepressant actions.
A single dose of NV-5138, a small molecule that modulates sestrin and crosses the blood-brain barrier, produced rapid and long-lasting antidepressant effects and quickly reversed anhedonia caused by chronic stress in mice. These effects required BDNF release in the medial prefrontal cortex, as blocking BDNF with an antibody or using a BDNF polymorphism that prevents activity-dependent release eliminated the behavioral responses. NV-5138 also rapidly increased synapse number and function in the medial prefrontal cortex and reversed synaptic deficits from chronic stress. The findings indicate that pharmacologically modulating sestrin activates mTORC1 signaling and BDNF release, offering a new approach for rapid-acting antidepressants.
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.