A single low dose of ketamine produces rapid and lasting antidepressant effects by blocking NMDA receptors containing the GluN2B subunit on specific GABA-releasing interneurons in the medial prefrontal cortex. Removing GluN2B from somatostatin-expressing interneurons prevented or masked ketamine's antidepressant actions and revealed sex-specific differences in excitatory signals onto principal neurons. The findings indicate that GluN2B-NMDA receptors on GABA interneurons are the initial cellular trigger for ketamine's rapid antidepressant effects.
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.
Tiam1, a protein that regulates the structure of synapses, drives hyperactivity in the anterior cingulate cortex (ACC) by reorganizing the actin cytoskeleton and stabilizing NMDA receptors. This maladaptive synaptic plasticity underlies depressive-like behaviors in mouse models of chronic pain. Low-dose ketamine, an NMDA receptor antagonist, produces sustained antidepressant-like effects by blocking Tiam1-mediated changes in ACC neurons. The findings identify Tiam1 as a key molecular factor linking chronic pain to depression and as a target for ketamine's long-lasting effects.
Societal perception of cannabis as low-risk is contradicted by rising THC potency and falling CBD levels, creating what the authors call a "perfect cannabis storm" of unprecedented neurodevelopmental harm, especially for vulnerable populations. Legalization, increased availability, and highly modified strains have produced cannabis today with exponentially higher THC concentrations than a decade ago, while protective cannabinoids like CBD have declined. The authors contend that these interrelated societal, political, and business factors have led to unmatched cannabis exposure in human history, challenging the view of cannabis as harmless.