Rapid-acting antidepressants ketamine and nitrous oxide converge on MAPK-DUSP signaling in the medial prefrontal cortex

Nitrous oxide (N2O; laughing gas) has recently been reported as a putative rapid-acting antidepressant, but little is known about the underlying mechanisms. We performed transcriptomics, in situ hybridization, and electrophysiological studies to examine the potential shared signatures induced by 1 h inhalation of 50% N2O and a single subanesthetic dose of ketamine in the medial prefrontal cortex (mPFC) in adult mice. Both treatments similarly affected the transcription of several negative regulators of mitogen-activated protein kinases (MAPKs), namely, dual specificity phosphatases. The effects were primarily located in the pyramidal cells. Notably, the overall effects of N2O on mRNA expression were much more prominent and widespread compared to ketamine. Ketamine caused an elevation of the spiking frequency of putative pyramidal neurons and increased gamma activity (30-100 Hz) of cortical local field potentials. However, N2O produced no such effects. Spiking amplitudes and spike-to-local field potential phase locking of putative pyramidal neurons and interneurons in this brain area showed no uniform changes across treatments. Thus, this study characterized the electrophysiological and transcriptome-wide changes in mPFC triggered by exposure to N2O and compared them with those caused by the rapid-acting antidepressant ketamine in terms of both the direction of their regulation and localization.