Trends in Neurosciences
ReviewCREB's control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models
Section snippets
CREB and memory: still a developing story
Several landmark articles in the 1990s 1, 2, 3 gave the cAMP response element binding protein (CREB) the title of ‘the memory gene’. Textbooks frequently depict CREB at the convergence of different activity-driven kinase pathways; downstream of different signaling cascades, such as the increase of intracellular cAMP after activation of G protein-coupled receptors, the increase of Ca2+ through activation of voltage- or ligand-gated channels, or the activation of receptor tyrosine kinases by
Regulation of intrinsic plasticity by CREB
Despite the large number of studies investigating the role of CREB in synaptic plasticity, research on the influence of CREB in neuronal activity per se were surprisingly lacking. Dong and colleagues addressed this question for the first time in a recent study that used recombinant Sindbis pseudovirions to genetically manipulate CREB activity in medium spiny neurons (MSNs) of the nucleus accumbens (NA) [17]. They found that the expression of a constitutively active CREB (ca-CREB) variant
Putative effector mechanisms
The intrinsic excitability of a neuron can be modulated by modifications in the threshold for firing an action potential, but also by changes in the properties of repeated firing. The specific mechanisms underlying CREB-mediated modulation of intrinsic excitability remain largely unknown, but seem distinct in different cell types. Both changes in the threshold and firing mode have been detected, although the identity of the conductances affected, and whether the changes occur through modulation
A novel view on the role of CREB in learning and memory processes
The role of CREB in memory formation and maintenance has been extensively investigated. Seminal studies in Aplysia and in Drosophila first identified the cAMP-signaling pathway as a core component of the molecular switch that converts short- to long-term memory 41, 42, 43. The demonstration of a direct role of CREB in memory formation and memory-related synaptic plasticity was provided years later by precise genetic or biochemical manipulation of CREB function in transgenic flies or cultured
Misregulation of CREB activity and altered excitability
In addition to the physiological roles outlined above, misregulation of intrinsic excitability by malfunction of CREB signaling might have important pathological consequences. Recent studies exploring the phenotype of various CREB mutant strains have revealed that CREB modulation of neuronal excitability can have important consequences in epileptogenesis. Thus, bitransgenic mice expressing the artificial CREB inhibitor A-CREB were more resistant to pentylenetetrazol (PTZ)-induced kindling and
Conclusion
Current evidence indicates that CREB activity modulates both intrinsic and synaptic plasticity. What is the relative weight of CREB-mediated modulation of intrinsic excitability and synaptic plasticity in memory formation? Is CREB primarily a ‘learning’ gene or a ‘memory’ gene? These questions need further exploration (see also Box 2). The schemes illustrating the putative role of CREB in memory should now consider not only the typical pathway leading to consolidation of synaptic plasticity
Acknowledgements
We thank Eloisa Herrera, Mikel Lopez de Armentia, Jose Lopez-Atalaya, Helene Marie, Matt Nolan and Luis M Valor for critical reading of the manuscript, and members of the Barco's lab for stimulating discussion. Research at AB's lab is supported by the Spanish Ministry of Science and Innovation Grants BFU2008-00611, SAF2008-03194-E and CSD2007-00023, and by grants from Fundación Ramón Areces and Fundació la Marató de TV3.
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