Clinical and preclinical studies indicate that early postnatal exposure to anesthetics can lead to lasting deficits in learning and other cognitive processes. The mechanism underlying this phenomenon has not been clarified and there is no treatment currently available. Recent evidence suggests that anesthetics might cause persistent deficits in cognitive function by disrupting key events in brain development. The hippocampus, a brain region that is critical for learning and memory, contains a large number of neurons that develop in the early postnatal period, which are thus vulnerable to perturbation by anesthetic exposure. Using an in vivo mouse model we demonstrate abnormal development of dendrite arbors and dendritic spines in newly generated dentate gyrus granule cell neurons of the hippocampus after a clinically relevant isoflurane anesthesia exposure conducted at an early postnatal age. Furthermore, we find that isoflurane causes a sustained increase in activity in the mechanistic target of rapamycin pathway, and that inhibition of this pathway with rapamycin not only reverses the observed changes in neuronal development, but also substantially improves performance on behavioral tasks of spatial learning and memory that are impaired by isoflurane exposure. We conclude that isoflurane disrupts the development of hippocampal neurons generated in the early postnatal period by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition.

临床和临床前研究表明，产后早期接触麻醉剂可导致学习和其他认知过程的持久缺陷。这种现象的潜在机制尚未阐明，目前尚无治疗方法。最近的证据表明，麻醉药可能会破坏大脑发育中的关键事件，从而导致认知功能的持续缺陷。海马是一个对学习和记忆至关重要的大脑区域，其中含有大量的神经元，这些神经元在产后早期发育，因此很容易受到麻醉剂暴露的干扰。使用体内小鼠模型，我们证明了在产后早期进行了临床相关的异氟醚麻醉后，海马新生成的齿状回颗粒细胞神经元中树突状树突和树突棘的异常发育。此外，我们发现异氟烷引起雷帕霉素途径的机械靶中活性的持续增加，并且雷帕霉素对该途径的抑制不仅逆转了观察到的神经元发育变化，而且还大大改善了在空间学习和学习的行为任务上的表现。异氟烷暴露会损害记忆力。