Calcium activation of cAMP and MAP kinase (MAPK) signaling is required for consolidation of hippocampus- dependent memories and also plays a pivotal role in other forms of neuroplasticity including long-lasting, long- term potentiation (L-LTP). This project focuses on mechanisms by which Ca2+ regulates MAPK and adenylyl cyclase during memory formation and the role of MAPK oscillations for the persistence of hippocampus-dependent memory. This proposal is based upon several discoveries made by our lab during the last funding period including the finding that SCOP, a neurospecific protein, attenuates MAPK activity and CRE-mediated transcription in hippocampal neurons. Furthermore, we discovered that SCOP is proteolyzed by calpain, a calcium-stimulated protease, during memory formation. We found that over expression of SCOP in the hippocampus blocks consolidation of memory for novel objects, without affecting acquisition or short-term memory. We hypothesize that calcium-stimulated degradation of SCOP may play an important role in other forms of neuroplasticity including spatial memory and L-LTP. We also discovered that MAPK, PKA, and MSK-1, a CREB kinase, are coactivated in the same subset of neurons in the area CA1 of the hippocampus during memory formation and that these signaling events are not stimulated during training in mice lacking calcium-stimulated adenylyl cyclases (AC1 and AC8). Despite evidence supporting a role for cAMP, MAPK, and CREB-mediated transcription in memory consolidation, this hypothesis does not readily explain the duration of LTM which can persist well beyond the lifetime of gene products increased during memory formation. Therefore, we examined MAPK activity in the hippocampus over extended periods of time to determine if the pathway undergoes periodic reactivation. We discovered that cAMP, as well as MEK and MAPK activities undergo a circadian oscillation in the hippocampus. We hypothesize that the persistence of contextual fear memory may depend upon the circadian oscillation of this signaling pathway.

Public Health Relevance

Memory loss is associated with a number of human diseases including Alzheimer's disease and is generally associated with aging. This project focuses on molecular mechanisms underlying memory consolidation and persistence. Consequently, this research may identify new drug target sites that can be exploited to enhance long-term and short-term memory.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Stewart, Randall R
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University of Washington
Schools of Medicine
United States
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Luo, Jie; Chen, Xuanmao; Pan, Yung-Wei et al. (2015) The type 3 adenylyl cyclase is required for the survival and maturation of newly generated granule cells in the olfactory bulb. PLoS One 10:e0122057
Wang, Wenbin; Pan, Yung-Wei; Zou, Junhui et al. (2014) Genetic activation of ERK5 MAP kinase enhances adult neurogenesis and extends hippocampus-dependent long-term memory. J Neurosci 34:2130-47
Chen, Ying-Zhang; Friedman, Jennifer R; Chen, Dong-Hui et al. (2014) Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia. Ann Neurol 75:542-9
Saraf, Amit; Luo, Jie; Morris, David R et al. (2014) Phosphorylation of eukaryotic translation initiation factor 4E and eukaryotic translation initiation factor 4E-binding protein (4EBP) and their upstream signaling components undergo diurnal oscillation in the mouse hippocampus: implications for memory per J Biol Chem 289:20129-38
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
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
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
Chen, Xuanmao; Xia, Zhengui; Storm, Daniel R (2012) Stimulation of electro-olfactogram responses in the main olfactory epithelia by airflow depends on the type 3 adenylyl cyclase. J Neurosci 32:15769-78
Pan, Yung-Wei; Chan, Guy C K; Kuo, Chay T et al. (2012) Inhibition of adult neurogenesis by inducible and targeted deletion of ERK5 mitogen-activated protein kinase specifically in adult neurogenic regions impairs contextual fear extinction and remote fear memory. J Neurosci 32:6444-55

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