N1 cassette-lacking NMDA receptors mediate the antidepressant activity of ketamine
bioRxiv Preprint Server April 12, 2025 Alina T. He, Wenbo Zhang, Hongbin Li et al. preprint
Ketamine is a fast-acting antidepressant, but how it works is unclear. A key question is whether NMDA receptors (NMDARs), which ketamine blocks, are responsible. Alternative splicing of the GluN1 subunit produces two versions: GluN1a (without exon 5) and GluN1b (with exon 5). In mice, ketamine blocked long-term potentiation (LTP) in the hippocampus only in GluN1a mice, not GluN1b mice. Although ketamine inhibited synaptic NMDARs in both types, GluN1a receptors remained blocked during neuronal firing while GluN1b receptors escaped blockade. Ketamine produced an antidepressant effect in GluN1a mice but not in GluN1b mice. GluN1a-containing NMDARs are selectively responsible for ketamine's antidepressant effect.