背景:标准抗抑郁治疗通常需要数周才能达到疗效,对许多患者无效。(R,S)-氯胺酮,一种N-甲基-D-天冬氨酸(NMDA)拮抗剂,已被证明是一种快速作用的抗抑郁药,并在给药后几小时内减轻抑郁症状。虽然先前的研究表明NMDA受体(NMDAR)的GluN2B亚基对内侧前额叶皮质(mPFC)中间神经元的重要性,尚无研究调查表达GluN2B的成人出生颗粒细胞(abGC)的影响。
方法:这里,我们检查了(R,S)-氯胺酮的功效取决于这些成年海马神经元使用遗传策略从雄性和雌性小鼠的巢蛋白细胞中选择性地消融NMDAR的GluN2B亚基,在一系列标准行为测定中进行测试。
结果:我们报道,在雄性小鼠中,6周龄成人出生神经元上的GluN2B表达是必需的(R,S)-氯胺酮对强迫游泳测试(FST)中的行为绝望和新颖性抑制进食(NSF)范式中的低吞食的影响,以及上下文恐惧条件(CFC)后的恐惧行为。在雌性老鼠中,GluN2B的表达对于NSF中对低吞食症的影响是必需的。当从2周龄的成年出生的神经元中消融GluN2B时,这些作用没有被复制。我们还发现,消融神经发生会增加CFC中的恐惧表达,由(R,S)-氯胺酮给药。
结论:与以前的研究一致,这些结果表明,表达GluN2B的6周龄成年海马神经元部分调节(R,S)-氯胺酮的速效作用。针对这些6周龄成年神经元的未来工作可能会对提高(R,S)-氯胺酮。
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.