PSD-95/kalirin-7/Rac1信号通路在七氟烷致幼期大鼠远期学习记忆能力损害中的作用

Sevoflurane, a commonly used volatile anesthetic, can produce long-term learning and memory disabilities in infant rats. Postsynaptic density-95 (PSD-95)/Discs large/Zona occludens-1(PDZ) domain is one of a molecular target for inhaled anesthetics. The PSD-95/Kalirin-7/Rac1 signaling pathway mediates hippocampal neurogenesis and synaptogenesis regulated by NMDA receptors and therefore affects learning and memory maturation. In our preliminary studies, we found sevoflurane down-regulated the expression of Kalirin-7, and thus suppressed its binding to PSD-95. In this proposal, we hypothesized that PSD-95/Kalirin-7/Rac1 signaling pathway may contribute to the underlying mechanisms of long-term learning and memory impairment dependent on hippocampus induced by early sevoflurane exposure. To address this, we will mainly focus on PND7 rats, and prepare animal model of long-term cognitive impairment induced by sevoflurane. We will also use gene transfection and RNA interfering techniques to modulate the expressions of PSD-95 and Kalirin-7.And we will also investigate the effects and underlying mechanisms of PSD-95/Kalirin-7/Rac1 signaling pathway in the process of long-term learning and memory impairment induced by early seveflurane exposure. The data from the proposed studies will shed new light on the evidence for interfering and therapy to long-term cognitive dysfunction induced by neonatal anesthetic exposure.

儿科麻醉常用药物七氟烷可损害幼期大鼠远期的学习记忆功能。PSD-95 PDZ结构域是氟烷类麻醉药物作用靶点之一。PSD-95/Kalirin-7/Rac1信号途径介导NMDA受体对海马兴奋性突触发育的调控作用，影响学习记忆能力成熟。我们预实验发现七氟烷下调Kalirin-7表达、抑制PSD-95与Kalirin-7结合。我们推测PSD-95/kalirin-7/Rac1信号通路参与七氟烷麻醉致幼期大鼠远期海马依赖的学习记忆损害机制。为此我们以出生后7天大鼠为主要研究对象，建立七氟烷麻醉致远期学习记忆功能损害模型，利用基因转染、RNA干扰等技术，调控PSD-95和Kalirin-7的表达，通过行为学、分子和亚细胞水平观察，探讨PSD-95/Kalirin-7/Rac1信号通路在七氟烷致幼期大鼠远期海马依赖的学习记忆损害中的作用及机制，为婴幼儿吸入麻醉致学习记忆损害的干预治疗提供思路和依据。