Memory Enhancement by A Genetic Increase in cAMP Signals

描述(申请人提供)：包括阿尔茨海默氏症和鲁宾斯坦-塔比综合征在内的几种人类疾病的特征是记忆缺陷。开发药物来增强受损患者的记忆力，可能会对这些患者和其他有记忆缺陷的患者的生活质量产生重大影响。来自几个实验室的证据表明，使用环核苷酸磷酸二酯酶(PDE)的抑制剂来增加大脑中的cAMP可以增强小鼠的记忆力。另一个有希望的药物靶点是AC1，它是一种神经特异性腺苷环化酶，它受活性依赖的钙增加的刺激，特别是在大脑中增加cAMP。为了从遗传学上验证这一观点，我们利用Ipha-Cam Kinase II启动子，让小鼠在海马区过表达AC1。这些转基因小鼠(AC1+)表现出对新对象的LTP和记忆的增强，以及上下文记忆消失率的降低。初步数据表明，记忆的增加可能是由于通过MAPK途径增强的信号。这些数据表明，AC1可能是增强记忆形成的一个药理“机会之窗”，这一可能性很有趣。这项资助的主要目的是确定为什么AC1+小鼠具有更好的记忆力。我们假设AC1+小鼠表现出记忆增强，这是由于AC1独特的调节特性，包括它对钙的敏感性以及Gs偶联受体和钙的协同激活。我们假设AC1+小鼠对新的物体表现出更好的记忆，因为训练诱导的Cre介导的转录更强大。这可能是由于训练诱导的MAPK活性放大、MAPK核移位或突触后去极化所致。我们还提出，大脑中AC1活性的遗传增强可以克服与鲁宾斯坦-塔比综合征相关的记忆缺陷，鲁宾斯坦-塔比综合征是一种由CREB结合蛋白(CBP)截短形式引起的遗传病。

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).