Memory Enhancement by A Genetic Increase in cAMP Signals

描述（由申请人提供）：包括阿尔茨海默氏症和鲁宾斯坦-泰比综合征在内的几种人类疾病都以记忆缺陷为特征。增强受损患者记忆的药物的开发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（PDEs）抑制剂来增加大脑中的cAMP，可以增强小鼠的记忆。另一个有希望在大脑中特异性增加cAMP的药物靶点是AC1，这是一种神经特异性腺苷酸环化酶，它被活性依赖性钙增加刺激。为了从遗传学上验证这一想法，我们使用Ipha-CaM激酶II启动子使小鼠在海马中过度表达AC1。这些转基因小鼠（AC1+）表现出增强的LTP和对新物体的记忆，以及降低的情境记忆消失率。初步数据表明，记忆的增加可能是由于通过MAPK途径增强的信号传导。这些数据显示了一种有趣的可能性，即AC1可能是增强记忆形成的药理学“机会之窗”。这项拨款的主要目的是确定为什么AC1+小鼠具有优越的记忆力。我们假设AC1+小鼠表现出记忆增强是因为AC1独特的调节特性，包括其钙敏感性和gs偶联受体和钙的协同激活。我们假设AC1+小鼠对新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活性扩增，MAPK核易位或突触后去极化。我们还提出，大脑中AC1活性的遗传增强可能克服与Rubinstein-Taybi综合征（一种由CREB结合蛋白（CBP）的截断形式引起的遗传性疾病）相关的记忆缺陷。

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).