An inhibitor of DNA recombination blocks memory consolidation, but not reconsolidation, in context fear conditioning.
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-beta-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.
Colón-Cesario
Melissa
M
Department of Biology, University of Puerto Rico, San Juan, 00931-3360, Puerto Rico.
Wang
Jianpeng
J
Ramos
Xiomara
X
García
Hermes G
HG
Dávila
Jorge J
JJ
Laguna
Jessenia
J
Rosado
Claribel
C
Peña de Ortiz
Sandra
S
D000818:Animals; D001085:Arabinofuranosylcytosine Triphosphate / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D011088:DNA Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007858:Learning / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D011995:Recombination, Genetic / Q000187:drug effects / Q000502:physiology*
D019384:Nucleic Acid Synthesis Inhibitors; D001085:Arabinofuranosylcytosine Triphosphate; D004247:DNA; D011088:DNA Ligases