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.

Public Health Relevance

The brain has the remarkable ability to process and store enormous amounts of information. Consequently, there is intense interest in molecular mechanisms underlying the formation and persistence of memory. Memory loss associated with aging and neurodegenerative diseases including Alzheimer's disease is devastating, not only to the patient but also the patient's family. This grant focuses on the molecular mechanisms for memory formation and the persistence of long-term memory. In the last grant period, we identified a potential molecular target for memory improvement, a calcium-sensitive adenylyl cyclase, AC1. This enzyme generates signals at the synapses in the brain, which leads to memory trace. We made a transgenic mouse over-expressing AC1 in mouse brain. This mouse strain has superior memory. The objectives of this grant are to understand why AC1 is required for memory and why AC1 over-expressing mice have superior memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH073601-07
Application #
8197421
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Asanuma, Chiiko
Project Start
2005-04-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
7
Fiscal Year
2012
Total Cost
$383,741
Indirect Cost
$133,741
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wardlaw, Sarah M; Phan, Trongha X; Saraf, Amit et al. (2014) Genetic disruption of the core circadian clock impairs hippocampus-dependent memory. Learn Mem 21:417-23
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Luo, Jie; Phan, Trongha X; Yang, Yimei et al. (2013) Increases in cAMP, MAPK activity, and CREB phosphorylation during REM sleep: implications for REM sleep and memory consolidation. J Neurosci 33:6460-8
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Hwang, Christopher K; Chaurasia, Shyam S; Jackson, Chad R et al. (2013) Circadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells. J Neurosci 33:14989-97
Pan, Yung-Wei; Storm, Daniel R; Xia, Zhengui (2013) Role of adult neurogenesis in hippocampus-dependent memory, contextual fear extinction and remote contextual memory: new insights from ERK5 MAP kinase. Neurobiol Learn Mem 105:81-92
Wang, Zhenshan; Phan, Trongha; Storm, Daniel R (2011) The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia. J Neurosci 31:5557-61
Zhang, Ming; Storm, Daniel R; Wang, Hongbing (2011) Bidirectional synaptic plasticity and spatial memory flexibility require Ca2+-stimulated adenylyl cyclases. J Neurosci 31:10174-83
Sindreu, Carlos; Palmiter, Richard D; Storm, Daniel R (2011) Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory. Proc Natl Acad Sci U S A 108:3366-70
Xiao, Zhijie; He, Liqun; Takemoto, Minoru et al. (2011) Glomerular podocytes express type 1 adenylate cyclase: inactivation results in susceptibility to proteinuria. Nephron Exp Nephrol 118:e39-48

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