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Neural Plasticity
Volume 2012, Article ID 581291, 8 pages
Review Article

Molecular Determinants of the Spacing Effect

1Department of Physiology, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4
2Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4

Received 25 October 2011; Revised 16 December 2011; Accepted 16 January 2012

Academic Editor: Andrew Weeks

Copyright © 2012 Faisal Naqib et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Long-term memory formation is sensitive to the pattern of training sessions. Training distributed over time (spaced training) is superior at generating long-term memories than training presented with little or no rest interval (massed training). This spacing effect was observed in a range of organisms from invertebrates to humans. In the present paper, we discuss the evidence supporting cyclic-AMP response element-binding protein 2 (CREB), a transcription factor, as being an important molecule mediating long-term memory formation after spaced training. We also review the main upstream proteins that regulate CREB in different model organisms. Those include the eukaryotic translation initiation factor (eIF2α), protein phosphatase I (PP1), mitogen-activated protein kinase (MAPK), and the protein tyrosine phosphatase corkscrew. Finally, we discuss PKC activation and protein synthesis and degradation as mechanisms by which neurons decode the spacing intervals.