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.

Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats

“…The results of the present study suggest that isoflurane activates NF-κB following mitochondrial dysfunction and CaN activation, and CaN is an upstream regulator of NF-κB activation. A complex interaction between CaN and NF-κB has been reported previously (32,33). CaN may dephosphorylate Bcl-10, which leads to IKKβ phosphorylation, IκBα degradation, RelA nuclear translocation and DNA binding in T helper cells (19).…”

Requirement of NF-kappa B Activation in Different Mice Brain Areas during Long-Term Memory Consolidation in Two Contextual One-Trial Tasks with Opposing Valences

“…The hippocampus has been described to be involved in context associative memories (Smith and Bulkin, 2014) and the dynamics of the activation of NF-kappa B during memory consolidation in this and other paradigms has been widely reported (Freudenthal et al, 2005; de la Fuente et al, 2014, 2015; Salles et al, 2015; Zalcman et al, 2015). Specifically, the transcription factor NF-kappa B has been described to be necessary for memory consolidation in several species such as crabs and mice (Freudenthal and Romano, 2000; Freudenthal et al, 2005).…”

Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer

“…However, SASP exerts many effects in addition to its ability to interfere with xCT function, so it cannot be considered a specific xCT inhibitor (39). Although recent preclinical models demonstrated that SASP impairs cancer growth and metastatic spread via xCT inhibition (15,17,40), its use in cancer patients is hampered by its low specificity, short bio-availability, and numerous side effects (41).…”