A single dose of inhaled nitrous oxide (N2O) rapidly and specifically activates layer V (L5) pyramidal neurons in the prefrontal cortex of rodents exposed to chronic stress. This activation reverses a stress-linked hypoactivity state, persists after N2O exposure, and is necessary for the antidepressant effect. The activation occurs independently of NMDA-receptor function and synaptic activity, contrary to N2O's purported mechanism. Instead, N2O inhibits calcium-sensitive potassium (SK2) channels, driving both rapid and sustained L5 activity and antidepressant-like effects. The findings suggest a novel molecular target for fast-acting antidepressants.
A single dose of inhaled nitrous oxide (N2O) rapidly activates layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress, rescuing a stress-associated hypoactivity state. This activation persists after exposure and is necessary for N2O's antidepressant-like effects. Although N2O is believed to act primarily through NMDA-receptor antagonism, L5 neurons activate even when NMDA-receptor function is blocked. Instead, N2O-induced inhibition of calcium-sensitive potassium (SK2) channels drives specific L5 activity and the ensuing antidepressant-like effects. These results indicate that N2O's fast antidepressant action relies on novel molecular actions in distinct cortical cell types.