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 subanesthetic dose of ketamine suppresses somatostatin-expressing (SST) interneurons in the medial prefrontal cortex of awake mice, leading to deficient dendritic inhibition. This causes greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, the authors show that this dendritic inhibitory mechanism affects frontal cortex-dependent behaviors and cortico-cortical connectivity. The results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as key local-circuit alterations driven by subanesthetic ketamine.
Major depressive disorder (MDD) is a common neuropsychiatric disease with limited treatment options that take weeks to work. Recent breakthroughs show that drugs like ketamine and scopolamine produce rapid and long-lasting antidepressant effects in MDD patients. Preclinical work in rodents indicates these effects arise from increased extracellular glutamate, elevated BDNF, activation of the mTORC1 cascade, and increased spine synapses in the prefrontal cortex (PFC). Both drugs work through converging molecular and cellular mechanisms in the PFC, antagonizing inhibitory interneurons to disinhibit pyramidal neurons, boosting glutamate. Specific NMDA and muscarinic acetylcholine receptor subtypes on GABAergic interneurons are promising targets for new rapid-acting antidepressants.
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.