Memory Enhancement by a Genetic Increase in cAMP Signals

描述（由申请人提供）：海马体依赖性记忆的巩固依赖于从头转录和翻译。巩固海马体依赖记忆所需的转录途径之一是CRE介导的转录。钙调素（CaM）刺激的腺苷酸环化酶和Erk/MAP激酶（MAPK）在记忆形成过程中cre介导的钙活化转录中起主要作用。本研究的重点是cam刺激的腺苷酸环化酶在记忆中的作用，以及在前脑过表达AC1的小鼠（AC1+小鼠）表现出的记忆增强机制。这是基于本实验室所做的几个观察，包括发现cam刺激的腺苷酸环化酶是巩固海马体依赖记忆所必需的，以及远程上下文记忆的持久性。我们还发现，在上下文记忆形成过程中，核易位和MAPK的激活取决于cam刺激的腺苷酸环化酶。我们发现，情境记忆的持久性可能是由海马中cAMP/MAPK/MSK1/CREB转录途径的昼夜节律振荡维持的，这种振荡依赖于cam刺激的腺苷酸环化酶。因此，我们在AC1+小鼠前脑中构建了过表达AC1的转基因小鼠品系。年轻的AC1+小鼠对新事物的记忆和社会识别能力更强，并且具有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不如野生型老年鼠，但在年轻AC1+小鼠中不受影响。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的激活和核易位，以及维持记忆所需的海马中MAPK活性的昼夜节律振荡。我们提出年轻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放大。我们提出海马中MAPK的昼夜节律振荡可能是由于海马中cam刺激的腺苷酸环化酶的昼夜节律振荡。

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.