MECHANISMS RESPONSIBLE FOR COGNITIVE IMPAIRMENT CAUSED BY EXPOSURE TO PCBS

因接触多氯联苯而导致认知障碍的机制

• 批准号: 6504070
• 负责人: DAVID Orlo CARPENTER
• 金额: $ 23.08万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6504070
• 关键词: calcium flux; cellular pathology; central neural pathway /tract; cholinergic receptors; developmental neurobiology; dopamine; electrophysiology; environmental toxicology; flow cytometry; free radicals; glutamate receptor; halobiphenyl /halotriphenyl compound; hippocampus; laboratory rat; learning; long term potentiation; membrane potentials; memory; mossy fiber; neural plasticity; neurotransmitter transport; protein kinase C; thyroid function

PCBs are known to have a variety of effects on the nervous system, but one of the potentially most serious is the decrement in cognitive potential that has been reported in children having elevated body burdens. The goal of this investigation is to determine whether PCBs alter a variety of neuronal processes in a animal model system that are known to be important in learning and memory. We propose to use acute and chronic exposure to Aroclor 1248 and four single PCB congeners, and a combination of electrophysiologic and flow cytometric techniques. The major hypothesis to be tested is the PCBs will reduce or block the process of long-term potentiation (LTP), which is one of the best available model systems for learning and memory. If this is the case, and our preliminary results suggest that it is, we will attempt to determine the mechanism(s) of action responsible. Using electrophysiological recordings, we will study synaptic transmission in two hippocampal circuits, the Schaffer collateral-CA1 pathway and the mossy fiber-CA3 pathway. We will investigate normal transmitter release and post-synaptic responses and several indicators of neuronal plasticity [pot-tetanic potentiation (PTP, LTP, paired pulse potentiation, phorbol ester-induced potentiation]. We expect to find a selective action on one or more of these complex responses, and if so, we will attempt to determine the mechanism. We will investigate effects on responses to specific neurotransmitter receptors (N-methyl-D-aspartate, acetylcholine), various kinases, including protein kinase C and calcium entry and/or release. In order to directly monitor calcium we will use cerebellar granule neurons studies in a flow cytometer, and determine whether there are direct effects of PCBs on calcium flux, as well as effects of PCBs on calcium entry or release triggered by five different pathways. We will monitor effects of PCBs on membrane potential changes and on generation of free radicals in the cells by different pathways. If effects are found, we will attempt to determine which congeners are responsible, whether the effects are mediated via interference with thyroid function or dopamine depletion, or whether some whether mechanism is responsible.

众所周知，多氯联苯对神经系统有多种影响，但有一种