A single dose of inhaled nitrous oxide (N2O) rapidly and durably activates a specific population of neurons in the cingulate cortex of rodents exposed to chronic stress. This activation rescues a stress-induced hypoactivity state in layer V (L5) pyramidal neurons and is necessary for N2O's antidepressant-like effects. Although N2O is believed to work primarily by blocking NMDA receptors, L5 neurons still activate when NMDA receptor function is inhibited. Instead, N2O inhibits calcium-sensitive potassium (SK2) channels, driving L5 neuron activity and antidepressant-like effects. These findings identify a novel molecular and circuit mechanism for N2O's fast antidepressant action.
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.