Nitrous Oxide activates layer 5 prefrontal cortical neurons via SK2 channel inhibition for antidepressant effect

Abstract

Abstract Nitrous oxide (N2O) induces rapid and durable antidepressant effects in patients suffering from treatment-resistant depression1,2. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled N2O induces rapid and specific activation of layer V (L5) pyramidal neurons in the prefrontal cortex of rodents exposed to chronic stress conditions. N2O-induced L5 activation rescues a stress-associated hypoactivity state, persists following N2O exposure, and is necessary for its antidepressant action. While NMDA-receptor (NMDA-R) antagonism has been N2O’s purported mechanism of action, L5 neurons activate independently from NMDA-R function and synaptic activity. By examining different molecular targets controlling excitability and cortical circuit elements, we identify N2O-induced inhibition of calcium-sensitive potassium (SK2) channels as a primary molecular interaction responsible for driving both rapid and persistent L5 activity along with its ensuing antidepressant-like effects. These results suggest that N2O-induced L5 activation is crucial for its fast antidepressant action and this effect involves novel and specific molecular actions with SK2 channels expressed in specific L5 cell types.