BackgroundKetamine has been reported to cause neonatal neurotoxicity in a variety of developing animal models. Various studies have been conducted to study the mechanism of neurotoxicity for general anesthetic use during the neonatal period. Previous experiments have suggested that developmentally generated granule neurons in the hippocampus dentate gyrus (DG) supported hippocampus-dependent memory. Therefore, this study aimed to investigate whether ketamine affects the functional integration of developmentally generated granule neurons in the DG. For this purpose,the postnatal day 7 (PND-7) Sprague-Dawley (SD) rats were divided into the control group and the ketamine group (rats who received 4 injections of 40 mg/kg ketamine at 1 h intervals). To label dividing cells, BrdU was administered for three consecutive days after the ketamine exposure; NeuN+/BrdU+cells were observed by using immunofluorescence. To evaluate the developmentally generated granule neurons that support hippocampus-dependent memory, spatial reference memory was tested by using Morris Water Maze at 3 months old, after which the immunofluorescence was used to detect c-Fos expression in the NeuN+/BrdU+ cells. The expression of caspase-3 was measured by western blot to detect the apoptosis in the hippocampal DG.ResultsThe present results showed that the neonatal ketamine exposure did not influence the survival rate of developmentally generated granule neurons at 2 and 3 months old, but ketamine interfered with the integration of these neurons into the hippocampal DG neural circuits and caused a deficit in hippocampal-dependent spatial reference memory tasks.ConclusionsIn summary, these findings may promote more studies to investigate the neurotoxicity of ketamine in the developing brain.

中文翻译：

---

氯胺酮影响成年阶段发育产生的颗粒神经元的整合

背景据报道，氯胺酮会在多种发育中的动物模型中引起新生儿神经毒性。已经进行了各种研究来研究新生儿期全身麻醉剂的神经毒性机制。先前的实验表明，海马齿状回（DG）中发育产生的颗粒神经元支持海马依赖性记忆。因此，本研究旨在探讨氯胺酮是否影响 DG 中发育生成的颗粒神经元的功能整合。为此，将出生后第7天（PND-7）Sprague-Dawley（SD）大鼠分为对照组和氯胺酮组（每隔1小时注射4次40 mg/kg氯胺酮的大鼠）。为了标记分裂细胞，在接触氯胺酮后连续三天施用 BrdU；采用免疫荧光法观察NeuN+/BrdU+细胞。为了评估发育中产生的支持海马依赖性记忆的颗粒神经元，在3个月大时使用莫里斯水迷宫测试空间参考记忆，之后使用免疫荧光检测NeuN+/BrdU+细胞中c-Fos的表达。Western blot检测海马DG细胞凋亡情况，检测caspase-3的表达。结果本研究结果显示，新生儿氯胺酮暴露不影响2、3月龄发育生成颗粒神经元的存活率，但氯胺酮干扰随着这些神经元整合到海马 DG 神经回路中，并导致海马依赖性空间参考记忆任务的缺陷。 结论 总之，这些发现可能会促进更多的研究来调查氯胺酮对发育中大脑的神经毒性。