Effects of nitrous oxide and ketamine on electrophysiological and molecular responses in the prefrontal cortex of mice: A comparative study

Nitrous oxide (N₂O; laughing gas) has recently reported to produce rapid antidepressant effects, 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 (10 mg/kg, i.p.) 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 (DUSPs). 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. Our findings suggest that N₂O and subanesthetic-dose ketamine target MAPK pathway in the mPFC but produce varying acute electrophysiological responses.