CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning

Mizuno, Makoto; Yamada, Kiyofumi; Maekawa, Naoya; Seishima, Mitsuru; Nabeshima, Toshitaka

doi:10.1016/s0166-4328(01)00470-3

Cited by 191 publications

(133 citation statements)

References 40 publications

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“…Since CREB is a downstream target of these cascades, the coincident activation of ERK1/2 and CREB induced by fear conditioning was expected. However, available data so far only revealed the coincident activation of both ERK1/2 and CREB (Cammarota et al 2000;Swank and Sweatt 2001;Wang et al 2004), or failed to demonstrate any simultaneous activation (Schulz et al 1999;Mizuno et al 2002) or functional coupling after learning (Kanterewicz et al 2000). More consistent was the result that inhibition of ERK1/2 activation leads to the blockade of CREB activation as well (Davis et al 2000;Zhang et al 2003).…”

Section: Functional Coupling Between Erk1/2 and Crebmentioning

confidence: 99%

Foreground contextual fear memory consolidation requires two independent phases of hippocampal ERK/CREB activation

Trifilieff¹,

Herry²,

Vanhoutte³

et al. 2006

Learn. Mem.

138

124

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Fear conditioning is a popular model for investigating physiological and cellular mechanisms of memory formation. In this paradigm, a footshock is either systematically associated to a tone (paired conditioning) or is pseudorandomly distributed (unpaired conditioning). In the former procedure, the tone/shock association is acquired, whereas in the latter procedure, the context/shock association will prevail. Animals with chronically implanted recording electrodes show enhanced amplitude of the extracellularly recorded field EPSP in CA1 pyramidal cells for up to 24 h after unpaired, but not paired, fear conditioning. This is paralleled by a differential activation of the ERK/CREB pathway in CA1, which is monophasic in paired conditioning (0-15 min post-conditioning), but biphasic (0-1 h and 9-12 h post-conditioning) in unpaired conditioning as revealed by immunocytochemistry and Western blotting. Intrahippocampal injection of the MEK inhibitor U0126 prior to each phase prevents the activation of both ERK1/2 and CREB after unpaired conditioning. Block of any activation phase leads to memory impairment. We finally reveal that the biphasic activation of ERK/CREB activity is independently regulated, yet both phases are critically required for the consolidation of long-term memories following unpaired fear conditioning. These data provide compelling evidence that CA1 serves different forms of memory by expressing differential cellular mechanisms that are dependent on the training regime.

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Section: Functional Coupling Between Erk1/2 and Crebmentioning

confidence: 99%

Foreground contextual fear memory consolidation requires two independent phases of hippocampal ERK/CREB activation

Trifilieff¹,

Herry²,

Vanhoutte³

et al. 2006

Learn. Mem.

138

124

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“…These activity changes trigger post-translational modifications of proteins initiating and sustaining multiple signal transduction pathways. In turn, these signaling pathways regulate changes in synaptic strength and connectivity by governing gene expression and protein translation (5)(6)(7)(8)(9)(10)(11)(12)(13). Depending on time elapsed since triggering of long-term synaptic plasticity, protein synthesis may be limited to the dendrites directly involved in the plasticity processes (14 -18).…”

mentioning

confidence: 99%

“…Depending on time elapsed since triggering of long-term synaptic plasticity, protein synthesis may be limited to the dendrites directly involved in the plasticity processes (14 -18). Multiple synaptic activity-dependent signal transduction pathways (7)(8)(9)(10)(11)(12)(13)19) orchestrate the regulation of synaptic plasticity on the translational level (for review see (20,21)). Accumulated evidence shows that different types of LTM depend on protein synthesis, disregarding dependence on brain regions such as amygdala (22,23), hippocampus (24 -29), and medial prefrontal or insular cortex ((30 -32); for review see (33)).…”

mentioning

confidence: 99%

Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation

Borovok

Nesher

Levin

et al. 2016

Molecular & Cellular Proteomics

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Spatial memory depends on the hippocampus, which is particularly vulnerable to aging. This vulnerability has implications for the impairment of navigation capacities in older people, who may show a marked drop in performance of spatial tasks with advancing age. Contemporary understanding of long-term memory formation relies on molecular mechanisms underlying long-term synaptic plasticity. With memory acquisition, activity-dependent changes occurring in synapses initiate multiple signal transduction pathways enhancing protein turnover. This enhancement facilitates de novo synthesis of plasticity related proteins, crucial factors for establishing persistent long-term synaptic plasticity and forming memory engrams. Extensive studies have been performed to elucidate molecular mechanisms of memory traces formation; however, the identity of plasticity related proteins is still evasive. In this study, we investigated protein turnover in mouse hippocampus during long-term spatial memory formation using the reference memory version of radial arm maze (RAM) paradigm. We identified 1592 proteins, which exhibited a complex picture of expression changes during spatial memory formation. Variable linear decomposition reduced significantly data dimensionality and enriched three principal factors responsible for variance of memory-related protein levels at (1) the initial phase of memory acquisition (165 proteins), (2) during the steep learning improvement (148 proteins), and (3) the final phase of the learning curve (123 proteins). Gene ontology and signaling pathways analysis revealed a clear correlation between memory improvement and learning phasecurbed expression profiles of proteins belonging to specific functional categories. We found differential enrichment of (1) Long-term synaptic plasticity is considered a cellular correlate of long-term memory (LTM) 1 . Contemporary understanding of memory formation is based on the initiation and maintenance of long-term synaptic plasticity (1-4), for which de novo protein synthesis is a vital requirement. De novo protein synthesis itself is secondary to activity-dependent changes in synapses that occur during learning processes. These activity changes trigger post-translational modifications of proteins initiating and sustaining multiple signal transduction pathways. In turn, these signaling pathways regulate changes in synaptic strength and connectivity by governing gene expression and protein translation (5-13). Depending on time elapsed since triggering of long-term synaptic plasticity, protein synthesis may be limited to the dendrites directly involved in the plasticity processes (14 -18). Multiple synaptic From the ‡Department

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“…In particular, the role of CREB in spatial navigation remains controversial. Numerous studies have shown that spatial memory formation is associated with increased CREB phosphorylation within the hippocampus (Mizuno et al 2002;Colombo et al 2003;Moncada and Viola 2006;Porte et al 2008). Also supporting a role for CREB in hippocampal-dependent spatial memory, mice homozygous for a deletion of the a and d isoforms of CREB were originally reported to have a specific deficit in longterm memory revealed in several memory tasks, including the Morris water maze (Bourtchuladze et al 1994).…”

mentioning

confidence: 99%

Chronic enhancement of CREB activity in the hippocampus interferes with the retrieval of spatial information

Viosca¹,

Malleret²,

Bourtchouladze³

et al. 2009

Learn. Mem.

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The activation of cAMP-responsive element-binding protein (CREB)-dependent gene expression is thought to be critical for the formation of different types of long-term memory. To explore the consequences of chronic enhancement of CREB function on spatial memory in mammals, we examined spatial navigation in bitransgenic mice that express in a regulated and restricted manner a constitutively active form of CREB, VP16-CREB, in forebrain neurons. We found that chronic enhancement of CREB activity delayed the acquisition of an allocentric strategy to solve the hidden platform task. The ability to turn on and off transgene expression allowed us to dissect the role of CREB in dissociable memory processes. In mice in which transgene expression was turned on during memory acquisition, turning off the transgene reestablished the access to the memory trace, whereas in mice in which transgene expression was turned off during acquisition, turning on the transgene impaired memory expression in a reversible manner, indicating that CREB enhancement specifically interfered with the retrieval of spatial information. The defects on spatial navigation in mice with chronic enhancement of CREB function were not corrected by conditions that increased further CREB-dependent activation of hippocampal memory systems, such as housing in an enriched environment. These results along with previous findings in CREB-deficient mutants indicate that the relationship of CREB-mediated plasticity to spatial memory is an inverted-U function, and that optimal learning in the water maze requires accurate regulation of this pathway.

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CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning

Cited by 191 publications

References 40 publications

Foreground contextual fear memory consolidation requires two independent phases of hippocampal ERK/CREB activation

Foreground contextual fear memory consolidation requires two independent phases of hippocampal ERK/CREB activation

Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation

Chronic enhancement of CREB activity in the hippocampus interferes with the retrieval of spatial information

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