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

Nitrous oxide (N2O) has shown promise as a putative rapid-acting antidepressant but little is known about the underlying mechanisms. We have here performed transcriptomics and electrophysiological studies to dissect shared signatures acutely induced by 1-hour inhalation of 50% N2O and single subanesthetic dose of ketamine, a well-established antidepressant, in the adult mouse medial prefrontal cortex. Unbiased quantitative RNA sequencing demonstrated that several transcripts belonging to the mitogen-activated protein kinase (MAPK) pathway are similarly regulated by N2O and ketamine. In particular, both treatments increased the expression of the dual specificity phosphatases (DUSPs), negative regulators of MAPKs. N2O also rapidly reduced saccharine preference and induced expression of Dusp1 and Dusp6 in animals subjected to chronic treatment with stress hormone corticosterone. Interestingly, overall, the effects of N2O on the mRNA expression were more prominent and widespread compared to ketamine. Ketamine and to lesser extent nitrous oxide caused elevation of gamma-activity (30-100 Hz) of cortical local field potential, however firing rate and phase locking of spike-to-LFPs of neurons of this brain area showed no uniform changes across the treatments. These findings provide support for the antidepressant properties of N2O and further highlight the involvement of MAPK regulation in the mechanism of action of rapid-acting antidepressants.