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The Journal of Neuroscience, May 17, 2006, 26(20):5524-5533; doi:10.1523/JNEUROSCI.3050-05.2006

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Behavioral/Systems/Cognitive
An Inhibitor of DNA Recombination Blocks Memory Consolidation, But Not Reconsolidation, in Context Fear Conditioning

Melissa Colón-Cesario, Jianpeng Wang, Xiomara Ramos, Hermes G. García, Jorge J. Dávila, Jessenia Laguna, Claribel Rosado, and Sandra Peña de Ortiz

Department of Biology, University of Puerto Rico, San Juan, Puerto Rico 00931-3360

Correspondence should be addressed to Dr. Sandra Peña de Ortiz, Department of Biology, University of Puerto Rico, P.O. Box 23360, San Juan, PR 00931-3360. Email: sandra{at}hpcf.upr.edu

Genomic recombination requires cutting, processing, and rejoining of DNA by endonucleases, polymerases, and ligases, among other factors. We have proposed that DNA recombination mechanisms may contribute to long-term memory (LTM) formation in the brain. Our previous studies with the nucleoside analog 1--D-arabinofuranosylcytosine triphosphate (ara-CTP), a known inhibitor of DNA ligases and polymerases, showed that this agent blocked consolidation of conditioned taste aversion without interfering with short-term memory (STM). However, because polymerases and ligases are also essential for DNA replication, it remained unclear whether the effects of this drug on consolidation were attributable to interference with DNA recombination or neurogenesis. Here we show, using C57BL/6 mice, that ara-CTP specifically blocks consolidation but not STM of context fear conditioning, a task previously shown not to require neurogenesis. The effects of a single systemic dose of cytosine arabinoside (ara-C) on LTM were evident as early as 6 h after training. In addition, although ara-C impaired LTM, it did not impair general locomotor activity nor induce brain neurotoxicity. Importantly, hippocampal, but not insular cortex, infusions of ara-C also blocked consolidation of context fear conditioning. Separate studies revealed that context fear conditioning training significantly induced nonhomologous DNA end joining activity indicative of DNA ligase-dependent recombination in hippocampal, but not cortex, protein extracts. Finally, unlike inhibition of protein synthesis, systemic ara-C did not block reconsolidation of context fear conditioning. Our results support the idea that DNA recombination is a process specific to consolidation that is not involved in the postreactivation editing of memories.

Key words: DNA recombination; DNA ligase; protein synthesis; fear conditioning; consolidation; reconsolidation; nonhomologous DNA end joining

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Received July 22, 2005; revised March 26, 2006; accepted March 27, 2006.

Correspondence should be addressed to Dr. Sandra Peña de Ortiz, Department of Biology, University of Puerto Rico, P.O. Box 23360, San Juan, PR 00931-3360. Email: sandra{at}hpcf.upr.edu

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