Memory Enhancement by A Genetic Increase in cAMP Signals

通过 cAMP 信号的遗传增强增强记忆

• 批准号: 7048100
• 负责人: DANIEL R STORM
• 金额: $ 33.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048100
• 关键词: AMPA receptors; G protein coupled receptor kinase; adenylate cyclase; biological signal transduction; cAMP response element binding protein; calcium; chromosome translocation; cyclic AMP; gene expression; genetic regulatory element; genetic transcription; genetically modified animals; laboratory mouse; memory; memory disorders; mitogen activated protein kinase; phosphodiesterases

DESCRIPTION (provided by applicant): Several human diseases including Alzheimer's and Rubinstein-Taybi syndrome are characterized by memory defects. The development of drugs to enhance the memory of compromised patients could have a major impact on the quality of life for these patients and others with memory defects. Evidence from several labs indicates that memory in mice may be enhanced using inhibitors of cyclic nucleotide phosphodiesterases (PDEs) to increase cAMP in the brain. Another promising drug target site to increase cAMP specifically in the brain is AC1, a neurospecific adenylyl cyclase that it is stimulated by activity-dependent calcium increases. To test this idea genetically, we made mice overexpressing AC1 in the hippocampus using the Ipha-CaM Kinase II promoter. These transgenic mice (AC1+) show enhanced LTP and memory for novel objects as well as a reduced rate of contextual memory extinction. Preliminary data indicate that the gain in memory may be due to enhanced signaling through the MAPK pathway. These data suggest the interesting possibility that AC1 may be a pharmacological "window of opportunity" to enhance memory formation. The major objective of this grant is to determine why AC1+ mice have superior memory. We hypothesize that AC1+ mice show memory enhancement because of the unique regulatory properties of AC1 which include its calcium sensitivity and synergistic activation by Gs-coupled receptors and calcium. We hypothesize that AC1+ mice show superior memory for novel objects because of more robust training- induced CRE-mediated transcription. This may be due to training-induced amplification MAPK activity, MAPK nuclear translocation, or postsynaptic depolarizations. We also propose that genetic enhancement of AC1 activity in the brain may overcome memory defects associated with Rubinstein-Taybi syndrome, a genetic disease due to a truncated form of the CREB binding protein (CBP).

描述（由申请人提供）：包括阿尔茨海默病和鲁宾斯坦-泰比综合征在内的几种人类疾病的特征是记忆缺陷。开发增强受损患者记忆力的药物可能会对这些患者和其他记忆缺陷患者的生活质量产生重大影响。多个实验室的证据表明，使用环核苷酸磷酸二酯酶 (PDE) 抑制剂增加大脑中的 cAMP 可以增强小鼠的记忆力。另一个有前景的专门增加大脑中 cAMP 的药物靶位点是 AC1，这是一种神经特异性腺苷酸环化酶，它受到活性依赖性钙增加的刺激。为了从基因上测试这个想法，我们使用 Ipha-CaM 激酶 II 启动子制作了在海马体中过度表达 AC1 的小鼠。这些转基因小鼠 (AC1+) 显示出增强的 LTP 和对新事物的记忆力，以及情境记忆消退率的降低。初步数据表明，记忆力的增强可能是由于 MAPK 通路的信号传导增强所致。这些数据表明了一个有趣的可能性，即 AC1 可能是增强记忆形成的药理学“机会之窗”。这笔资助的主要目的是确定为什么 AC1+ 小鼠具有出色的记忆力。我们假设 AC1+ 小鼠表现出记忆增强，因为 AC1 独特的调节特性，包括其钙敏感性以及 Gs 偶联受体和钙的协同激活。我们假设 AC1+ 小鼠对新事物表现出优异的记忆力，因为训练诱导的 CRE 介导的转录更加强大。这可能是由于训练引起的 MAPK 活性放大、MAPK 核易位或突触后去极化所致。我们还提出，大脑中 AC1 活性的遗传增强可能会克服与 Rubinstein-Taybi 综合征相关的记忆缺陷，Rubinstein-Taybi 综合征是一种由 CREB ​​结合蛋白 (CBP) 截短形式引起的遗传性疾病。