Memory Enhancement by a Genetic Increase in cAMP Signals

描述(申请人提供)：海马体依赖记忆的巩固依赖于从头转录和翻译。巩固海马区依赖记忆所需的转录途径之一是Cre-，介导的转录。在记忆形成过程中，钙调素(CaM)刺激的腺苷环化酶，以及Erk/MAP激酶(MAPK)在Cre介导的转录的钙激活中起主要作用。这项建议侧重于CaM刺激的腺苷环化酶在记忆中的作用，以及在前脑过度表达AC1的小鼠(AC1小鼠)表现出的增强记忆的机制。它是基于这个实验室的几个观察结果，包括发现CaM刺激的腺苷环化酶对于巩固海马体依赖的记忆以及远程上下文记忆的持久性是必需的。我们还发现，在情境记忆形成过程中，MAPK的核转位和激活依赖于CaM刺激的腺苷环化酶。我们发现，海马区cAMP/MAPK/MSK1/CREB转录途径的昼夜振荡可能维持了情景记忆的持续性，这种振荡依赖于CaM刺激的腺苷环化酶。因此，我们建立了一个在前脑中过表达AC1的转基因小鼠株，即AC1小鼠。年轻的AC1小鼠对新事物和社会识别有更好的记忆力，以及更持久的远程上下文记忆。然而，老年AC1小鼠的空间记忆能力低于老年野生型小鼠，而年轻AC1小鼠的空间记忆能力则没有受到影响。我们认为，CaM刺激的腺苷酸环化酶活性是记忆巩固和记忆持久所必需的，因为它支持记忆形成过程中MAPK的激活和核转位，以及维持记忆所需的海马区MAPK活性的昼夜振荡。我们推测，幼年AC1小鼠表现出的更强的记忆可能是由于cAMP/MAPK/MSK-1/CREB信号通路的信号增强以及该通路的昼夜振荡的放大所致。我们推测，海马区MAPK的昼夜振荡可能是由于CaM刺激的海马腺苷酸环化酶的昼夜振荡所致。

DESCRIPTION (provided by applicant): Consolidation of hippocampus-dependent memory depends on de novo transcription and translation. One of the transcriptional pathways required for consolidation of hippocampus-dependent memory is CRE-,mediated transcription. Calmodulin (CaM)-stimulated adenylyl cyclases, and Erk/MAP kinase (MAPK) plays a major role in calcium activation of CRE-mediated transcription during formation of memory. This proposal focuses on the role of CaM-stimulated adenylyl cyclases in memory and the mechanism for enhanced memory exhibited by mice over-expressing AC1 in the forebrain (AC1+ mice). It is based upon several observations made by this lab including the discovery that CaM-stimulated adenylyl cyclases are required for consolidation of hippocampus-dependent memory, as well as the persistence of remote contextual memory. We also discovered that the nuclear translocation and activation of MAPK during contextual memory formation depends upon CaM-stimulated adenylyl cyclases. We found that the persistence of contextual memory may be maintained by the circadian oscillation of the cAMP/MAPK/MSK1/CREB transcriptional pathway in the hippocampus, an oscillation which depends upon CaM-stimulated adenylyl cyclases. Therefore, we made a transgenic mouse strain over-expressing AC1 in the forebrain, AC1+ mice. Young AC1+ mice have superior memory for novel objects and social recognition and more persistent remote contextual memory. However, the spatial memory of old AC1+ mice is inferior to old wild-type littermates, yet unaffected in young AC1+ mice. We propose that CaM-stimulated adenylyl cyclase activity is required for memory consolidation and memory persistence because it supports the activation and nuclear translocation of MAPK during memory formation and the circadian oscillation of MAPK activity in the hippocampus required to maintain memory. We propose that the stronger memory exhibited by young AC1+ mice may be due to enhanced signaling through the cAMP/MAPK/ MSK-1/CREB signaling pathway as well as amplification of the circadian oscillation of this pathway. We propose that the circadian oscillation of MAPK in the hippocampus may be due to circadian oscillation of CaM-stimulated adenylyl cyclases in the hippocampus.