Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses

Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this lag remains unclear. Laughing gas (N2O), another NMDA-R (N-methyl-d-aspartate receptor) blocker, has been reported to bring antidepressant effects rapidly upon drug discontinuation. We took advantage of the exceptional pharmacokinetic properties of N2O to investigate EEG (electroencephalogram) alterations and molecular determinants of antidepressant actions during and immediately after NMDA-R blockade. Effects of the drugs on brain activity were investigated in C57BL/6 mice using quantitative EEG recordings. Western blot and qPCR were used for molecular analyses. Learned helplessness (LH) was used to assess antidepressant-like behavior. Immediate-early genes (e.g., bdnf) and phosphorylation of mitogen-activated protein kinasemarkers of neuronal excitabilitywere upregulated during N2O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3 (glycogen synthase kinase 3) became regulated only gradually upon N2O discontinuation, during a brain state dominated by slow EEG activity. Subanesthetic ketamine and flurothyl-induced convulsions (reminiscent of electroconvulsive therapy) also evoked slow oscillations when their acute pharmacological effects subsided. The correlation between ongoing slow EEG oscillations and TrkB-GSK3 signaling was further strengthened utilizing medetomidine, a hypnotic-sedative agent that facilitates slow oscillations directly through the activation of (2)-adrenergic autoreceptors. Medetomidine did not, however, facilitate markers of neuronal excitability or produce antidepressant-like behavioral changes in LH. Our results support a hypothesis that transient cortical excitability and the subsequent regulation of TrkB and GSK3 signaling during homeostatic emergence of slow oscillations are critical components for rapid antidepressant responses