小鼠成体颗粒细胞上的 GluN2B 可调节(R,S)-氯胺酮的速效作用。

IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY International Journal of Neuropsychopharmacology Pub Date : 2024-10-01 DOI:10.1093/ijnp/pyae036
Nicholas E Bulthuis, Josephine C McGowan, Liliana R Ladner, Christina T LaGamma, Sean C Lim, Claire X Shubeck, Rebecca A Brachman, Ezra Sydnor, Ina P Pavlova, Dong-Oh Seo, Michael R Drew, Christine A Denny
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引用次数: 0

摘要

背景:标准的抗抑郁治疗通常需要数周时间才能见效,对许多患者无效。(N-甲基-D-天冬氨酸(NMDA)拮抗剂--(R,S)-氯胺酮已被证明是一种速效抗抑郁剂,可在用药后数小时内减轻抑郁症状。以往的研究表明,NMDA 受体(NMDAR)的 GluN2B 亚基对内侧前额叶皮层(mPFC)的中间神经元非常重要,但还没有研究调查过表达 GluN2B 的成体颗粒细胞(abGCs)的影响。方法:在此,我们采用一种遗传策略,选择性地消减雄性和雌性小鼠 Nestin+ 细胞中的 NMDAR GluN2B 亚基,并通过一系列标准行为测定进行了测试,从而研究了(R,S)-氯胺酮的药效是否取决于这些成体海马神经元:我们报告说,在雄性小鼠中,(R,S)-氯胺酮对强迫游泳试验(FST)中的行为绝望和新奇性抑制摄食(NSF)范例中的食欲减退以及情境恐惧条件反射(CFC)后的恐惧行为的影响需要6周大的成体神经元上的GluN2B表达。在雌性小鼠中,GluN2B的表达是影响NSF食欲减退的必要条件。在消减 2 周大的成体神经元中的 GluN2B 时,这些效应并没有得到复制。我们还发现,消减神经发生会增加 CFC 中的恐惧表达,而服用(R,S)-氯胺酮可以缓冲恐惧表达:与之前的研究一致,这些结果表明,表达 GluN2B 的 6 周龄成体海马神经元部分调节了(R,S)-氯胺酮的速效作用。未来针对这些6周大的成神经元开展的工作可能会被证明有利于提高(R,S)-氯胺酮的疗效。
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GluN2B on Adult-Born Granule Cells Modulates (R,S)-Ketamine's Rapid-Acting Effects in Mice.

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) 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.

Methods: 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.

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 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.

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.

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来源期刊
CiteScore
8.40
自引率
2.10%
发文量
230
审稿时长
4-8 weeks
期刊介绍: The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.
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