(R,S)-ketamine's rapid-acting antidepressant effects are modulated by NR2B- containing NMDA receptors on adult-born hippocampal neurons

Abstract

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 NR2B subunit of the NMDA receptor (NMDAR) on interneurons in the medial prefrontal cortex (mPFC), no study has investigated the influence of NR2B-expressing adult-born granule cells (abGCs). In this study, we examined whether (R,S)-ketamines efficacy depends upon these adult-born hippocampal neurons using a genetic strategy to selectively ablate the NR2B subunit of the NMDAR from Nestin+ cells. To validate our findings, we also used several other transgenic lines including one in which NR2B was deleted from an interneuron (Parvalbumin (PV)+) population. We report that in male mice, NR2B expression on 6-week-old adult-born neurons is necessary for (R,S)-ketamines 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, NR2B expression is necessary for effects on hyponeophagia in the NSF. We also find that ablating neurogenesis increases fear expression in CFC, which is buffered by (R,S)-ketamine administration. In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing NR2B partially modulate (R,S)-ketamines rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of (R,S)-ketamines antidepressant actions.