低剂量铅暴露在小胶质细胞对神经突触修饰中的作用及机制研究

Studies have confirmed that lead is highly neurotoxic. It can cause brain damage and cognitive defects in children at very low doses. Microglia is a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system (CNS). Recent studies demonstrated that microglia paly more roles more than an immune cell in CNS, in physiological condition, microglia are conformed be a key role in synaptic stripping and formation. In the process of lead exposure-induced cognitive impairment and normal synaptic dysfunction, microglia may lose their normal function on synaptic caused by lead exposure and then play an important rolein this cognitive impairment and synaptic dysfunction. Based on preliminary studies we propose the following hypothesis: low dose lead exposure can produce neurotoxicity, resulting in learning and memory dysfunction; low doses of lead exposure on cognitive disfunction may both implicated with redundant synaptic pruning abnormal and new synaptic formation abnormal, while this process maybe a key point on lead induced neurotoxicity and cognitive impairment; microglia may be interfed by low-dose lead exposure and lose their normal function on synaptic stripping and formation in the process of lead induced neurotoxicity and cognitive impairment, which ultimately leads to learning and memory dysfunction. It will be benefit on further understanding the mechanism of lead induced cognitive disfunction and provide new protective methods if we can clarify the effect of microglia dysfunction on lead induced neurotoxicity and learning and memory injury and its molecular mechanism.

铅具有很强的神经毒性，在极低剂量时也可引起儿童认知缺陷。小胶质细胞是CNS免疫细胞，研究显示，小胶质细胞在生理状况下也不可或缺。如对冗余突触的修剪；促进新突触生成等。在铅暴露诱导认知损伤及正常突触功能障碍的过程中，小胶质细胞可能因铅暴露导致功能异常从而可能发挥了重要的作用。基于前期研究我们提出如下假设：①低剂量铅暴露可以产生神经毒性，导致学习记忆功能损害；②低剂量铅暴露对认知功能的损伤可能同时涉及到冗余突触修剪功能的障碍及新突触生成功能的障碍；而这一过程的异常可能是铅导致神经毒性及认知损伤的重要环节；③小胶质细胞在上述损伤过程中可能是低剂量铅暴露干扰了小胶质细胞对冗余突触的修剪以及对新突触生成的促进作用，从而最终导致学习记忆功能损害。若能够证实小胶质细胞功能异常在铅暴露所致神经毒性及学习记忆能力损伤中的作用，阐明其分子机制，将对进一步阐明铅对认知损伤的机制及防护措施具有重要意义。

铅具有很强的神经毒性，在极低剂量时也可引起儿童认知缺陷。小胶质细胞是CNS免疫细胞，研究显示，小胶质细胞在生理状况下也不可或缺，如对冗余突触的修剪，促进新突触生成等。在铅暴露诱导认知损伤及正常突触功能障碍的过程中，小胶质细胞可能因铅暴露导致功能异常从而可能发挥了重要的作用。本项目在研究中逐步阐明铅在孕期以及哺乳期进入子代大脑后可诱导大脑海马区域小胶质细胞活化，而与小胶质细胞活化同时出现的还有突触修饰的启动蛋白CX3CR1的高表达以及由神经元分泌的，介导突触修剪的神经元相关蛋白fractalkine的高表达；研究结果还提示铅暴露有可能通过小胶质细胞活化介导了突触修剪相关蛋白高表达以及突触生成相关蛋白表达水平的降低，从而在动物学习过程中无法有效生成新的突触并最终导致认知功能的障碍。为验证这一假设，进一步深入研究采用了米诺环素拮抗小胶质细胞活化，阐明在显著拮抗小胶质细胞活化以及其活化产物的分泌后，突触修饰相关的几个关键蛋白：CX3CR1、fractalkine、TSP、SYP、C1q等表达水平的改变得到显著的逆转；动物的认知功能也得到显著逆转。体内实验还采用了外源性补硒来干预铅在孕期及哺乳期在子代体内的吸收，同时硒又具有强大的抗氧化损伤作用，其结果亦能保护子代认知功能在一定程度上免于损伤，但其确切机制仍需进一步深入研究。本研究深入阐述了铅暴露导致认知功能损伤的新的发病机制，为铅暴露的损伤预防研究提供了新的切入点和研究思路。本研究截止目前已发表标注资助的SCI论文2篇。获得国家发明专利2项，实用新型专利1项。研究期间内正式出版了《神经毒理学》、《寒区军事医学》等2部国家级专著、教材。