镧所致氧化应激对于星形胶质细胞功能、神经元兴奋性和记忆的影响及其机制

Lanthanum possesses neurotoxicity and can impact cognitive function. However, the mechanism underlying these adverse effects is not clear. Our previous work has shown that astrocytic oxidative stress caused by lanthanum may be the starting point of neural toxic action and memory impairment by this chemical, thereby resulting in dysfunction of astrocytes which may interfere with the normal regulation of synaptic plasticity and neuronal excitability. Astrocytes serve as the integral part of neural system and modulate the activation level of NMDAR via synthesizing and releasing gliotransmitters such as glutamate, D-serine and ATP, regulating the content of glutamate in synaptic cleft,and also provide energy to neurons via lactate shuttle. Once these processes was disturbed, neuronal dysfunction and memory impairment would be the result. The purpose of this study is to validate the hypothesis mentioned above from the aspects of oxidative stress and active state of related signaling pathway, expression regulation of receptors, transporters, metabolic enzymes and antioxidases, synthesis and release level of excitatory transmitters, and extent of channel openning by experiments in vivo and vitro, with making use of techniques in neuroethology, electrophysiology, histopathology, immunohistochemistry, biochemistry and molecular biology. The results of this study will provide new experimental data for clarifying the mechanism underlying the neural toxic effects caused by lanthanum and searching the molecular target points of effective intervention.

镧具有神经毒性，影响认知功能，其机制尚未阐明。我们的前期工作提示，镧致星形胶质细胞（AC）氧化应激可能是其发挥神经毒作用、造成记忆损害的起点，由此导致AC功能障碍，干扰AC对于突触可塑性和神经元兴奋性的正常调控。AC作为神经系统的整合器，可通过合成、释放神经胶质递质谷氨酸、D-丝氨酸和ATP，控制突触间隙内的谷氨酸水平来调节NMDAR的激活程度并通过乳酸穿梭为神经元提供能量，如果这些过程发生紊乱，势必会影响神经元的功能，导致记忆受损。本研究拟采用体内、体外实验相结合的方法，运用神经行为学、神经电生理学、组织病理学、免疫组织化学、生物化学与分子生物学等技术手段，从氧化应激和相关信号通路活化状态，受体、转运体、代谢酶和抗氧化酶的表达调控，兴奋性递质的合成与释放水平以及离子通道的开放程度等不同层面、不同角度来验证上述假设，为阐明镧的神经毒作用机制和寻找有效干预的分子靶点提供新的实验资料。

镧可通过血脑屏障在脑内蓄积，造成神经元损伤，影响学习记忆功能，其机制尚未完全阐明。星形胶质细胞作为神经系统的整合器，可通过合成、释放谷氨酸、D-丝氨酸等神经胶质递质，控制突触间隙内的谷氨酸水平来调节神经元NMDA受体的激活程度并通过转运乳酸为神经元提供能量底物，如果这一过程发生紊乱，势必会影响神经元的功能，导致记忆受损。本研究通过整体动物与体外细胞试验相结合的方法, 应用神经行为学、神经电生理学、组织病理学、生物化学和分子生物学技术, 明确了氯化镧对大鼠学习记忆能力、海马CA1区L-LTP诱导与维持的有害影响及对神经元和神经突触超微结构的损害作用，证实镧可引起星形胶质细胞内钙超载使其兴奋性异常升高，增加谷氨酸和丝氨酸的合成与释放；下调Nrf 2信号通路抑制抗氧化酶的表达，造成星形胶质细胞氧化应激；干扰星形胶质细胞内糖原的合成与分解，减少乳酸合成及其向神经元的转运；破坏谷氨酸-谷氨酰胺循环，影响突触间隙谷氨酸的清除与代谢；由此导致神经元NMDA受体过度活化，诱发兴奋性毒性而致神经元发生凋亡/坏死。上述结果从新的视角揭示了镧损害学习记忆的机制，为有效干预镧的神经损害提供了新的科学线索和分子生物学靶点，对于防治镧乃至稀土元素引起的儿童智力低下和认知功能缺陷具有理论意义和实际应用价值。