Lasley S M, Gilbert M E
Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, Peoria 61656, USA.
Neurotoxicology. 2000 Dec;21(6):1057-68.
Epidemiological investigations have established the relationship between chronic developmental lead (Pb) exposure and cognitive impairments in young children, defining Pb neurotoxicity as a significant pediatric health problem. Exposed animals have proven to be effective models of this condition, exhibiting similar sensitivity to the actions of Pb and replicating abnormal learning behaviors in exposed children. Research has extended these observations in animals to identifying the processes underlying the cognitive dysfunction, utilizing the long-term potentiation (LTP) paradigm as a correlate of learning ability. Results from these studies have been in widespread agreement in reporting impairments in synaptic plasticity. Exposure-related changes consist of increases in LTP induction threshold, decreases in magnitude of potentiation, and shortened LTP duration. Furthermore, while LTP may be more readily affected by Pb during early development, exposure initiated after weaning also potently affects synaptic plasticity. Biphasic dose-effect relationships also appear in which impaired LTP is observed at intermediate exposure levels (27-62 microg/100 ml), but not at higher exposures. Investigation of the synaptic processes underlying LTP has provided additional insight into the bases of the impaired potentiation and diminished cognitive ability. Biochemical and neurophysiological approaches have found stimulated glutamate release to be diminished in hippocampus at blood Pb values where deficits in LTP have been observed. Multiple actions of Pb may be involved at this exposure level since animals exposed postweaning exhibited similar decrements in evoked glutamate release to those exposed continuously from conception, similar to the observations in measures of LTP. A biphasic dose-effect relationship was also found in which stimulated glutamate release in hippocampus was decreased at intermediate exposures, but not at higher levels. A direct inhibitory effect of Pb2+ on NMDA receptor function does not appear to occur at environmentally relevant exposure levels, but both exposure-induced increases and decreases in receptor density have been reported by different workers. Evidence from behavioral and neurophysiological investigations can be explained by increased NMDA receptor density on the bases of increased sensitivity to agonists and decreased sensitivity to antagonists. From this body of findings it is apparent that decreases in stimulated glutamate release are a significant contributing factor to the exposure-related changes seen in LTP. Furthermore, despite general agreement on the actions of Pb on synaptic plasticity, reports of exposure effects on NMDA receptor function have been relatively variable, suggesting either that the nature of the receptor changes are dependent on exposure conditions or that the receptors are secondarily affected by Pb actions produced at signal transduction or cellular loci.
流行病学调查已证实幼儿长期接触发育性铅（Pb）与认知障碍之间的关系，将铅神经毒性定义为一个重大的儿童健康问题。已证明暴露动物是这种情况的有效模型，对铅的作用表现出相似的敏感性，并重现暴露儿童的异常学习行为。研究已将这些动物观察结果扩展到确定认知功能障碍背后的过程，利用长时程增强（LTP）范式作为学习能力的相关指标。这些研究结果在报告突触可塑性受损方面已达成广泛共识。与暴露相关的变化包括LTP诱导阈值增加、增强幅度减小和LTP持续时间缩短。此外，虽然LTP在早期发育期间可能更容易受到铅的影响，但断奶后开始的暴露也会强烈影响突触可塑性。还出现了双相剂量效应关系，即在中等暴露水平（27 - 62微克/100毫升）观察到LTP受损，但在更高暴露水平则未观察到。对LTP背后的突触过程的研究为增强受损和认知能力下降的基础提供了更多见解。生化和神经生理学方法发现，在观察到LTP缺陷的血铅值时，海马体中刺激的谷氨酸释放减少。在这个暴露水平可能涉及铅的多种作用，因为断奶后暴露的动物与从受孕开始持续暴露的动物相比，诱发的谷氨酸释放减少程度相似，这与LTP测量中的观察结果相似。还发现了双相剂量效应关系，即在中等暴露水平时海马体中刺激的谷氨酸释放减少，但在更高水平则未减少。在环境相关暴露水平下，Pb2 +对NMDA受体功能似乎没有直接抑制作用，但不同研究人员报告了暴露引起的受体密度增加和减少情况。行为和神经生理学研究的证据可以通过对激动剂敏感性增加和对拮抗剂敏感性降低导致NMDA受体密度增加来解释。从这一系列研究结果来看，显然刺激的谷氨酸释放减少是LTP中与暴露相关变化的一个重要促成因素。此外，尽管关于铅对突触可塑性的作用已达成普遍共识，但关于暴露对NMDA受体功能影响的报告相对多变，这表明要么受体变化的性质取决于暴露条件，要么受体受到信号转导或细胞位点产生的铅作用的继发影响。
