title: Calcineurin phosphatase as a negative regulator of fear memory in hippocampus: control on nuclear factor-κB signaling in consolidation and reconsolidation.
abstract: Protein phosphatases are important regulators of neural plasticity and memory. Some studies support that the Ca(2+) /calmodulin-dependent phosphatase calcineurin (CaN) is, on the one hand, a negative regulator of memory formation and, on the other hand, a positive regulator of memory extinction and reversal learning. However, the signaling mechanisms by which CaN exerts its action in such processes are not well understood. Previous findings support that CaN negatively regulate the nuclear factor kappaB (NF-κB) signaling pathway during extinction. Here, we have studied the role of CaN in contextual fear memory consolidation and reconsolidation in the hippocampus. We investigated the CaN control on the NF-κB signaling pathway, a key mechanism that regulates gene expression in memory processes. We found that post-training intrahippocampal administration of the CaN inhibitor FK506 enhanced memory retention one day but not two weeks after training. Accordingly, the inhibition of CaN by FK506 increased NF-κB activity in dorsal hippocampus. The administration of the NF-κB signaling pathway inhibitor sulfasalazine (SSZ) impeded the enhancing effect of FK506. In line with our findings in consolidation, FK506 administration before memory reactivation enhanced memory reconsolidation when tested one day after re-exposure to the training context. Strikingly, memory was also enhanced two weeks after training, suggesting that reinforcement during reconsolidation is more persistent than during consolidation. The coadministration of SSZ and FK506 blocked the enhancement effect in reconsolidation, suggesting that this facilitation is also dependent on the NF-κB signaling pathway. In summary, our results support a novel mechanism by which memory formation and reprocessing can be controlled by CaN regulation on NF-κB activity.
authors.affiliation: Laboratorio de Neurobiología de la Memoria, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina; Instituto de Fisiología, Biología Molecular y Neurociencias, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
authors.forename: Verónica
authors.initials: V
authors.lastname: de la Fuente
authors.forename: Noel
authors.initials: N
authors.lastname: Federman
authors.forename: María Sol
authors.initials: MS
authors.lastname: Fustiñana
authors.forename: Gisela
authors.initials: G
authors.lastname: Zalcman
authors.forename: Arturo
authors.initials: A
authors.lastname: Romano
mesh_terms: D000818:Animals; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology; D003214:Conditioning, Classical / Q000502:physiology; D004597:Electroshock; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D008568:Memory / Q000502:physiology*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009483:Neuropsychological Tests; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012460:Sulfasalazine / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D002491:Central Nervous System Agents; D016328:NF-kappa B; D012460:Sulfasalazine; C120817:calcineurin phosphatase; D010744:Phosphoric Monoester Hydrolases; D016559:Tacrolimus
keywords: NF-κB; calcineurin; consolidation; fear conditioning; hippocampus; reconsolidation