MICROMAPPING OF LEAD INDUCED CHANGES TO NMDA RECEPTORS

描述（摘自候选人摘要） 铅的广泛使用已使铅暴露成为一个严重的环境问题， 职业危害 儿童特别容易受到 铅和接触铅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， 谷氨酸受体功能被铅下调， 调节减弱长时程增强（LTP），这是一种与 学习 最近的下调研究使用了结合测定法， 免疫细胞化学显示在铅后激动剂结合减少 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测定。 候选人将决定 铅如何用一种新的高分辨率方法改变NMDA受体功能 定位和表征受体功能的方法。 此方法使用本地 在活细胞中分离3 μ m膜部分的笼状激动剂的光解 在大脑切片中。 候选人将联合收割机全细胞电压钳 记录，局部光解和钙成像，以检查 NMDA受体下调对长时程增强和长时程 萧条 她假设铅通过以下方式降低NMDA受体功能： 降低功能性受体的表达，改变受体亚单位 组合物，并改变钙渗透性，从而减弱LTP和LTD。 这些实验将为下游的研究提供依据 由受体激活引发的过程。

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.