GluN2B on adult-born granule cells modulates (R,S)-ketamine's rapid-acting effects in mice.

ABSTRACT

BACKGROUND: Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the GluN2B subunit of the NMDA receptor (NMDAR) on interneurons in the medial prefrontal cortex (mPFC), no study has investigated the influence of GluN2B-expressing adult-born granule cells (abGCs). METHODS: Here, we examined whether (R,S)-ketamine's efficacy depends upon these adult-born hippocampal neurons using a genetic strategy to selectively ablate the GluN2B subunit of the NMDAR from Nestin+ cells in male and female mice, tested across an array of standard behavioral assays. RESULTS: We report that in male mice, GluN2B expression on 6-week-old adult-born neurons is necessary for (R,S)-ketamine's effects on behavioral despair in the forced swim test (FST) and on hyponeophagia in the novelty suppressed feeding (NSF) paradigm, as well on fear behavior following contextual fear conditioning (CFC). In female mice, GluN2B expression is necessary for effects on hyponeophagia in the NSF. These effects were not replicated when ablating GluN2B from 2-week-old adult-born neurons. We also find that ablating neurogenesis increases fear expression in CFC, which is buffered by (R,S)-ketamine administration. CONCLUSIONS: In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing GluN2B partially modulate (R,S)-ketamine's rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of (R,S)-ketamine.