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.
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.
Ketamine's rapid antidepressant effects depend on GluN2B-containing NMDA receptors on somatostatin-expressing (Sst) interneurons in the medial prefrontal cortex (mPFC). In mice, a single subanesthetic dose of ketamine reduced NMDA-induced burst firing of Sst-interneurons, decreased inhibitory transmission, and increased excitatory transmission in layer V pyramidal neurons, reversing behavioral deficits caused by chronic unpredictable stress. These effects were absent in mice lacking GluN2B from Sst-interneurons. The findings identify Sst-interneurons as the initial cellular trigger for ketamine's synaptic and behavioral actions, supporting the disinhibition hypothesis whereby ketamine disinhibits pyramidal neurons via GluN2B-NMDARs on Sst-interneurons, activating mTOR signaling and enhancing synaptic function.
Activating Drd1 dopamine receptor expressing pyramidal cells in the medial prefrontal cortex (mPFC) produces rapid and long-lasting antidepressant and anxiolytic responses in mice, whereas stimulating Drd2 expressing pyramidal cells does not affect anxiety-like or depression-like measures. Disrupting Drd1 activity also blocks the rapid antidepressant effects of ketamine. Stimulation of mPFC Drd1 terminals in the basolateral amygdala recapitulates the antidepressant effects of somatic stimulation. These findings identify specific cellular targets in the mPFC and downstream circuitry involved in rapid antidepressant responses.