PROTEIN PHOSPHORYLATION AND LTP IN AGED ANIMALS

老年人和患有阿尔茨海默病的人 一般都有严重的认知障碍 年龄相仿的动物 在学习和记忆方面也有严重的缺陷。 然而，在这方面， 直到最近才取得重大进展， 理解认知的分子和细胞基质 功能 因此，了解细胞和分子基础， 年龄相关的学习缺陷才刚刚开始出现。 长期 增强（LTP）是突触可塑性的一种形式， 被吹捧为学习和记忆的细胞构建块。 期间 上一个赠款期间，P. I.在LTP诱导中表现出明显的缺陷 在老年Fischer 344大鼠的CA 1区。 LTP的分子相关性是 这也是以往工作的重点。 私家侦探已经表明LTP诱导 刺激引起突触蛋白磷酸化增加， 囊泡相关磷蛋白，也表明老年动物 突触蛋白磷酸化的显著缺陷。 此外，P.I.和 他的同事们最近开发出了所需的免疫试剂， 研究NMDA和红藻氨酸/AMPA受体。 这些受体被认为 在LTP中起着关键作用，他们似乎在旧的LTP中有缺陷。 动物 在目前的建议中，以前关于年龄相关缺陷的工作， LTP机制将得到扩展，NMDA和红藻氨酸/AMPA的新研究 接收器已计划。 第二，PI。建议测试是否 治疗（热量限制和抗氧化剂治疗）， 据报道，随着年龄的增长， 或消除特定LTP机制中与年龄相关的缺陷。 这些 研究将涉及细胞和分子分析。 具体 重点将放在四个方面。 首先是私家侦探将检验一个假设 老年动物在齿状回和CA 3区的LTP诱导中表现出缺陷 海马区。 私家侦探然后将检验假设， 抗氧化剂治疗和/或热量限制可改善衰老 LTP诱导的相关缺陷。 第二，PI。建议测试 老年动物缺乏symapsin磷酸化的假说 由电生理刺激引起。 当发现缺陷时， 建议测试抗氧化剂治疗和/或热量限制 因为他们有能力改善这些赤字。 私家侦探建议测试 假设NMDA和/或红藻氨酸/AMPA受体功能、表达 和/或磷酸化在老年动物中改变。 如果与年龄相关 选择这些受体中任一种的缺陷，P.I.将考验 热量限制和/或抗氧化剂治疗可能 改善这些赤字。 在这项建议的最终目标，P.I. 将检验LTP诱导后激酶激活可能 缺乏年老的动物。 此外，PI。还提议 与项目1、2和4合作。 纯化的激酶和抗体将 为GABAA-R和Ca 2+通道功能的协同研究提供了条件 分别与项目1和项目2进行合作实验。 最后， 将测定突触蛋白I表达作为移植物的量度 与项目#4合作开发。

Aged individuals and individuals suffering from Alzheimer's disease typically have significant cognitive impairment. Similarly aged animals are also known to have profound deficits in learning and memory. However, it is only recently that significant progress has been made in understanding the molecular and cellular substrates of cognitive functioning. Thus an understanding of the cellular and molecular bases of age related-learning deficits is just beginning to emerge. Long-term potentiation (LTP) is a form of synaptic plasticity that has been widely touted as a cellular building block of learning and memory. During the previous grant period the P.I. demonstrated clear deficits in LTP induction in the CA1 area of aged Fischer 344 rats. Molecular correlates of LTP were also a major focus of previous work. The P.I. has shown that LTP-inducing stimuli produce an increase in the phosphorylation of synapsin a synaptic vesicle-associated phosphoprotein and has also shown that aged animals have significant deficits in synapsin phosphorylation. Moreover, The P.I. and his colleagues have recently developed the immunological reagents required to study the NMDA and kainate/AMPA receptors. These receptors are thought to play critical role in LTP and they appear to be defective in old animals. in the current proposal previous work on age-related deficits in LTP mechanisms will be extended and new studies of NMDA and kainate/AMPA receptors are planned. Second, the P.I. proposes to test whether treatments (caloric restriction an antioxidant therapy) which have been reported to ameliorate cognitive and other deficits seen with age may limit or eliminate age-related deficits in specific LTP mechanisms. These studies will involve both cellular and molecular analyses. The specific foci will be in four areas. First, the P.I. will test the hypothesis that aged animals will exhibit deficits in LTP induction in the dentate and CA3 regions of the hippocampus. The P.I. will then test the hypothesis that antioxidant treatment and/or caloric restriction may ameliorate age related-deficits in LTP induction. Second, the P.I. proposes to test the hypothesis that aged animals have deficits in symapsin phosphorylation induced by electrophysiological stimulation. When deficits are found it is proposed that antioxidant treatment and/or caloric restriction be tested for their ability to ameliorate these deficits. The P.I. proposes to test the hypothesis that NMDA and/or kainate/AMPA receptor function, expression and/or phosphorylation are altered in aged animals. If age related deficits in either of these receptors is selected, the P.I. will test the hypothesis that caloric restriction and/or antioxidant treatment may ameliorate these deficits. In the final aim of this proposal, the P.I. will test the hypothesis that kinase activation following LTP induction may be deficient in old animals. In addition, the P.I. also proposed to collaborate with Projects 1, 2 and 4. Purified kinases and antibodies will be provided for collaborative studies of GABAA-R and Ca2+ channel function in collaborative experiments with Projects 1 and 2 respectively. Lastly, synapsin I expression will be assayed as a measure of transplant development in collaboration with Project #4.