STIM2调控SOCE在慢性间歇缺氧所致的海马突触可塑性损伤和认知功能障碍中的作用及机制研究

Cognitive deficit is one of the major consequences of obstructive sleep apnea syndrome (OSAS). Several studies have shown that OSAS has adverse effects on learning, memory and attention. Chronic intermittent hypoxia (CIH) is the most characteristic pathophysiological change resulting from OSAS. The impairment of hippocampal synaptic plasticity is critical for cognitive deficits caused by CIH. The dendritic spines serve as the physical substrates for the hippocampal synaptic plasticity. Recent studies show that the stromal interaction molecule 2 (STIM2) mediated store-operated Ca2+ entry (SOCE) play an important role in the maintenance of the spines. Our research team spent years in the study of sleep respiratory disorders. Our recent data showed that the neuron damage and the synapse injury accompanied by a decrease of STIM2 expression in the hippocampus of CIH mice, indicating that the STIM2 may have an influence on the CIH-induced cognitive deficits. This research supposed to observe the hippocampal synaptic plasticity impairments and the cognitive deficits caused by CIH and the role of STIM2-SOCE in it. We will collect data from human beings and the CIH models in vitro and in vivo to study the mechanisms for hippocampal synaptic plasticity impairments induced by CIH and find whether STIM2 overexpression attenuate the damage. We hope our research will yield indepth understanding regarding the molecular mechanisms underlying the cognitive deficits of OSAS and provide novel treatment options for it.

阻塞性睡眠呼吸暂停综合征（OSAS）常继发认知功能障碍，主要表现在学习、记忆力、注意力等方面。慢性间歇缺氧（CIH）造成海马突触可塑性损伤是引起OSAS患者认知障碍的重要病理生理基础。突触后树突棘为突触可塑性的结构基础。基质相互作用分子 2（STIM2）调控的钙库操纵钙离子通道（SOCE）对树突棘长期稳定性的维持有重要意义。本研究者所在科研组常年从事睡眠呼吸疾病研究，在前期工作中发现CIH小鼠海马神经细胞、突触损伤，STIM2表达水平下降，提示STIM2可能在CIH所致认知损害中起到作用。本课题拟通过暴露于间歇缺氧环境的细胞及动物模型，结合人体研究，探讨STIM2调控的SOCE在CIH所致的突触可塑性异常、认知功能障碍中的作用，并利用基因工程技术阻滞、过表达STIM2后观察神经元突触可塑性损伤及认知功能的变化情况，以期为OSAS认知障碍机制的深入研究及治疗方案的选择提供借鉴思路。

睡眠呼吸暂停（OSAS）为常见睡眠呼吸障碍疾病，易导致认知损伤。慢性间歇缺氧（CIH）造成海马突触可塑性损伤是引起OSAS患者认知障碍的重要病理生理基础。基质相互作用分子 2（STIM2）调控对树突棘长期稳定性的维持有重要意义。本研究旨在探究STIM2在CIH所致的突触可塑性异常、认知功能障碍中的作用。本研究发现OSA患者存在轻度的认知功能障碍，其氧化应激水平增高。水迷宫实验提示CIH小鼠认知能力下降，其在平台的穿越次数及平台象限的停留时间均减少，CIH过表达STIM2组其认知能力改善。CIH组突触可塑性损伤，CIH+STIM2组改善。CIH小鼠海马中炎症因子及氧化应激增加，STIM2组改善。CH小鼠神经树突棘密度降低，而CI+STIM2组改善。CIH小鼠神经元中细胞器减少，凋亡增加，而CIH+STIM2组改善。本研究表明CIH可以导致炎症、氧化应激、神经突触受损、神经元损伤及凋亡，从而导致认知损害，过表达STIM2可改善CIH所致的突触可塑性异常，改善神经损伤，改善认知损害。