MICROMAPPING OF LEAD INDUCED CHANGES TO NMDA RECEPTORS

描述(摘自候选人的摘要) 铅的广泛使用使铅暴露成为一种严重的环境和 职业危害。儿童特别容易受到 铅和铅暴露会导致严重的认知和行为缺陷。 虽然铅是一种已知的环境神经毒素，但其生理基础 这种毒性仍不清楚。然而，有证据表明，NMDA型 谷氨酸受体功能被铅下调，而这一下调 调节减弱长时程增强(LTP)，长时程增强是一种与 学习。最近关于下调调控的研究使用了结合分析和 免疫细胞化学显示铅后激动剂的结合减少 治疗。虽然这些研究提供了有价值的信息，但它们不是 完整组织中受体的功能分析。候选人将决定 铅如何通过一种新的高分辨率方法改变NMDA受体的功能 对受体功能进行定位和表征。此方法使用本地 笼状激动剂光解分离活细胞3微米膜片 在脑片中。候选人将结合全电池电压钳位 记录，局部光解和钙成像，以检查 NMDA受体对长时程增强和长时程增强的下调作用 抑郁症。她假设铅通过以下方式降低NMDA受体的功能 减少功能性受体的表达，改变受体亚基 成分，改变钙的通透性，从而减弱LTP和LTD。 这些实验将为下游的检验提供依据。 由受体激活启动的过程。

DESCRIPTION (Taken from the Candidate's Abstract) The widespread use of lead has made lead exposure a serious environmental and occupational hazard. Children are particularly vulnerable to the effects of lead and exposure can cause serious cognitive and behavioral deficits. Although lead is a known environmental neurotoxin, the physiological bases of this toxicity remain unclear. However, evidence suggests that the NMDA-type glutamate receptor function is down-regulated by lead, and this down regulation attenuates long-term potentiation (LTP), a cellular correlate of learning. Recent studies of downregulation have used binding assays and immunocytochemistry to show that binding of agonist is reduced after lead treatment. While these studies provide valuable information, they are not functional assays of receptors in intact tissue. The candidate will determine how lead modifies NMDA receptor function with a novel, high resolution method of localizing and characterizing receptor function. This method uses local photolysis of caged agonists to isolate 3 um membrane sections in living cells within brain slices. The candidate will combine whole-cell voltage clamp recordings, local photolysis, and calcium imaging to examine the effect of NMDA receptor downregulation on long-term potentiation and long-term depression. She hypothesizes that lead decreases NMDA receptor function by decreasing expression of functional receptors, changing receptor subunit composition, and altering calcium permeability, which attenuates LTP and LTD. These experiments will provide a basis for examination of the downstream processes initiated by receptor activation.