GluN2A mediates ketamine-induced rapid antidepressant-like responses

Ketamine was thought to induce rapid antidepressant responses by inhibiting GluN2B-containing N-methyl-D-aspartic acid (NMDA) receptors (NMDARs), which presents a promising opportunity to develop better antidepressants. However, adverse side effects limit the broader application of ketamine and GluN2B inhibitors are yet to be approved for clinical use. It is unclear whether ketamine acts solely through GluN2B-dependent mechanisms. The present study reports that the loss of another major NMDAR subunit, GluN2A, in adult mouse brains elicits robust antidepressant-like responses with limited impact on the behaviors that mimic the psychomimetic effects of ketamine. The antidepressant-like behavioral effects of broad NMDAR channel blockers, such as ketamine and MK-801 (dizocilpine), were mediated by the suppression of GluN2A, but not by the inhibition of GluN2B. Moreover, treatment with ketamine or MK-801 rapidly increased the intrinsic excitability of hippocampal principal neurons through GluN2A, but not GluN2B. Together, these findings indicate that GluN2A mediates ketamine-triggered rapid antidepressant-like responses.