蛋白磷酸酶PP2A在幼年期七氟烷麻醉导致成年认知功能障碍中的作用与治疗机制研究

七氟烷麻醉对幼童神经发育及成年后脑功能的不良影响已引起学界关注。本课题组前期预实验发现幼年期七氟烷麻醉可造成海马蛋白磷酸酶PP2A表达的持续降低，且该现象与七氟烷引起Tau蛋白过度磷酸化密切相关。此外，DNA甲基化可引起PP2A活性下调，我们前期研究发现七氟烷导致Tau蛋白过度磷酸化与PP2A活性下调有关。据此，我们提出科学假说：七氟烷导致海马发育异常及远期认知功能障碍与DNA过度甲基化引起的海马PP2A活性下降有关。为此，本课题拟借助PP2A模型小鼠并通过表观遗传学、神经电生理等技术研究DNA甲基化及PP2A在七氟烷引起海马发育异常及远期认知功能障碍中的作用。再者，我们拟采用PP2A激动剂SMAPs观察其对七氟烷造成的海马发育异常及远期认知功能障碍的治疗作用及可能机制。该研究结果可为婴幼儿手术安全使用七氟烷提供理论依据，也可为开发神经保护药物防治该类病症提供重要参考。

The effects of sevoflurane anesthesia on childhood neurodevelopment and adult brain function have attracted increasing attention. Our preliminary experiments found that sevoflurane exposure during the neonatal period may cause continuous decrease of hippocampal expression of protein phosphatase PP2A, which is closely related to Tau hyperphosphorylation induced by sevoflurane. In addition, DNA methylation can down-regulate PP2A expression. Our previous study found that sevoflurane leads to Tau hyperphosphorylation and PP2A down-regulation. Based on these findings, we speculated that sevoflurane-induced hippocampal developmental abnormalities and long-term cognitive dysfunction are associated with the decreased hippocampal PP2A activity caused by DNA hypermethylation. To this end, we intend to investigate the role of DNA methylation and PP2A in sevoflurane-induced defects of hippocampal development and impairments of long-term cognition using PP2A mouse models and technologies including epigenetics and neuroelectrophysiology. Furthermore, we plan to use PP2A agonist SMAPs to study its effects and possible mechanisms on sevoflurane-induced hippocampal developmental defects and long-term cognitive impairments. This study can provide a theoretical basis for the safe use of sevoflurane in pediatric surgeries, and can provide a valuable reference for the development of relative neuroprotective drugs.