Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
Department of Anesthesiology, University of Colorado School of Medicine, 12401 East 17th Avenue, Aurora, CO, 80045, USA.
Mol Neurobiol. 2018 Jan;55(1):164-172. doi: 10.1007/s12035-017-0730-0.
Mounting evidence suggests that prolonged exposure to general anesthesia (GA) during brain synaptogenesis damages the immature neurons and results in long-term neurocognitive impairments. Importantly, synaptogenesis relies on timely axon pruning to select axons that participate in active neural circuit formation. This process is in part dependent on proper homeostasis of neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF). We set out to examine how GA may modulate axon maintenance and pruning and focused on the role of BDNF. We exposed post-natal day (PND)7 mice to ketamine using a well-established dosing regimen known to induce significant developmental neurotoxicity. We performed morphometric analyses of the infrapyramidal bundle (IPB) since IPB is known to undergo intense developmental modeling and as such is commonly used as a well-established model of in vivo pruning in rodents. When IPB remodeling was followed from PND10 until PND65, we noted a delay in axonal pruning in ketamine-treated animals when compared to controls; this impairment coincided with ketamine-induced downregulation in BDNF protein expression and maturation suggesting two conclusions: a surge in BDNF protein expression "signals" intense IPB pruning in control animals and ketamine-induced downregulation of BDNF synthesis and maturation could contribute to impaired IPB pruning. We conclude that the combined effects on BDNF homeostasis and impaired axon pruning may in part explain ketamine-induced impairment of neuronal circuitry formation.
越来越多的证据表明，在大脑突触发生过程中长时间暴露于全身麻醉（GA）会损害未成熟神经元，并导致长期神经认知障碍。重要的是，突触发生依赖于轴突修剪的时机，以选择参与活跃神经回路形成的轴突。这个过程部分依赖于神经营养因子的适当稳态，特别是脑源性神经营养因子（BDNF）。我们着手研究 GA 如何调节轴突维持和修剪，并专注于 BDNF 的作用。我们使用众所周知的、会引起明显发育神经毒性的剂量方案，使出生后第 7 天（PND7）的小鼠接触氯胺酮。我们对下锥体束（IPB）进行形态计量学分析，因为已知 IPB 经历强烈的发育建模，因此通常被用作啮齿动物体内修剪的成熟模型。当从 PND10 到 PND65 对 IPB 重塑进行跟踪时，我们注意到与对照组相比，在氯胺酮处理的动物中，轴突修剪出现延迟；这种损伤与氯胺酮诱导的 BDNF 蛋白表达和成熟下调相一致，这表明了两个结论：BDNF 蛋白表达的激增“信号”提示对照动物中 IPB 修剪强烈，而氯胺酮诱导的 BDNF 合成和成熟下调可能导致 IPB 修剪受损。我们得出结论，BDNF 动态平衡和受损轴突修剪的综合影响可能部分解释了氯胺酮诱导的神经元回路形成障碍。
