Department of Anesthesiology, Jiangning Hospital of Traditional Chinese Medicine, Nanjing, China.
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou, China.
BMC Neurosci. 2019 Dec 18;20(1):60. doi: 10.1186/s12868-019-0542-4.
Ketamine 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.
The 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.
In summary, these findings may promote more studies to investigate the neurotoxicity of ketamine in the developing brain.
氯胺酮已在多种发育中的动物模型中被报道可导致新生儿神经毒性。已有多项研究旨在研究新生儿期使用全身麻醉的神经毒性机制。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，本研究旨在研究氯胺酮是否会影响 DG 中发育产生的颗粒神经元的功能整合。为此，将出生后第 7 天（PND-7）的 Sprague-Dawley（SD）大鼠分为对照组和氯胺酮组（1 小时间隔接受 4 次 40mg/kg 氯胺酮注射的大鼠）。为了标记分裂细胞，在氯胺酮暴露后连续 3 天给予 BrdU；通过免疫荧光观察 NeuN+/BrdU+细胞。为了评估支持海马依赖性记忆的发育中产生的颗粒神经元，在 3 个月大时通过 Morris 水迷宫测试空间参考记忆，之后使用免疫荧光检测 NeuN/BrdU 细胞中的 c-Fos 表达。通过 Western blot 测量 caspase-3 的表达以检测海马 DG 中的细胞凋亡。
本研究结果表明，新生期氯胺酮暴露不会影响发育中产生的颗粒神经元在 2 个月和 3 个月时的存活率，但氯胺酮干扰了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缺陷。
总之，这些发现可能会促进更多的研究来调查氯胺酮在发育中的大脑中的神经毒性。
