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.
Chronic unpredictable stress in male rodents reduces GABAergic proteins and the frequency of inhibitory postsynaptic currents in layer V pyramidal neurons of the medial prefrontal cortex, accompanied by depression-like behaviors. A single dose of ketamine reverses these stress-induced deficits in GABA markers and depressive-like behaviors. The findings indicate that impairments of GABAergic synapses are key determinants of depressive behavior and that ketamine restores both GABA inhibitory and glutamate neurotransmission.
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.
Poor surgical outcomes after microvascular decompression for trigeminal neuralgia are linked to maladaptive central neural reorganization rather than ineffective surgery. Among 60 patients, those with poor outcomes showed enhanced functional connectivity between default mode, somatomotor, and control networks and subcortical limbic structures (amygdala, nucleus accumbens, hippocampus) compared to those with good outcomes. A classifier using these connections achieved 86% accuracy in distinguishing outcome groups. Longer disease duration correlated with decreased fractional anisotropy in sensorimotor white matter tracts. The findings suggest that pain becomes cognitively and affectively 'self-embedded', transitioning from a sensory event to a persistent self-referential narrative that sustains pain even after peripheral trigger removal, reframing some trigeminal neuralgia as a central network disorder.