Doctoral Program in Neurobiology and Behavior (NB&B), Columbia University, New York, New York, USA.
Department of Neuroscience, Barnard College, New York, New York, USA.
Int J Neuropsychopharmacol. 2024 Oct 1;27(10). doi: 10.1093/ijnp/pyae036.
Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) receptor 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 on interneurons in the medial prefrontal cortex, no study to our knowledge has investigated the influence of GluN2B-expressing adult-born granule cells.
Here, we examined whether (R,S)-ketamine's efficacy depends on adult-born hippocampal neurons using a genetic strategy to selectively ablate the GluN2B subunit of the NMDA receptor from Nestin+ cells in male and female mice, tested across an array of standard behavioral assays.
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 and on hyponeophagia in the novelty suppressed feeding paradigm, as well on fear behavior following contextual fear conditioning. In female mice, GluN2B expression is necessary for effects on hyponeophagia in novelty suppressed feeding. 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 contextual fear conditioning, 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 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.
标准的抗抑郁治疗通常需要数周才能见效，并且对许多患者无效。（R，S）-氯胺酮，一种 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，已被证明是一种快速作用的抗抑郁药，并能在给药后数小时内降低抑郁症状。虽然以前的研究表明 NMDA 受体的 GluN2B 亚基在中前额皮质的中间神经元中很重要，但据我们所知，没有研究调查过表达 GluN2B 的成年海马新生颗粒细胞的影响。
在这里，我们使用一种遗传策略来检查（R，S）-氯胺酮的疗效是否取决于成年海马神经元，该策略选择性地从雄性和雌性小鼠的巢蛋白+细胞中去除 NMDA 受体的 GluN2B 亚基，在一系列标准行为测定中进行测试。
我们报告说，在雄性小鼠中，6 周龄成年海马新生神经元上的 GluN2B 表达对于（R，S）-氯胺酮在强迫游泳试验中对行为绝望和新奇抑制进食范式中的低食欲以及在情境恐惧条件作用后对恐惧行为的影响是必要的。在雌性小鼠中，GluN2B 表达对于新奇抑制进食中的低食欲效应是必要的。当从 2 周龄成年海马新生神经元中去除 GluN2B 时，这些效应并未复制。我们还发现，去除神经发生会增加情境恐惧条件作用中的恐惧表达，而（R，S）-氯胺酮的给药会缓冲这种表达。
与以前的研究一致，这些结果表明，表达 GluN2B 的 6 周龄成年海马新生神经元部分调节（R，S）-氯胺酮的快速作用。未来针对这些 6 周龄成年海马新生神经元的研究可能有助于提高（R，S）-氯胺酮的疗效。
