The relationship between memory consolidation and reconsolidation at the molecular level is poorly understood. Here, we identify three immediate-early genes that are differentially regulated in the mouse hippocampus after contextual fear conditioning and reactivation of the context-shock memory: serum-and glucocorticoid-induced kinase 1 (SGK1), SGK3, and nerve growth factor-inducible gene B (NGFI-B). The upregulation of SGK1 expression was not specific for the context-shock association and therefore not suitable for a comparison of contextual memory consolidation and reconsolidation. SGK3 expression was upregulated during both consolidation and reconsolidation. Analysis of SGK3 expression showed that expression changes elicited by a context-shock association during consolidation can subsequently be recapitulated during reconsolidation and that the transcriptional changes induced by retrieval depend on the remoteness of the memory. On the other hand, we found that NGFI-B is regulated during consolidation but not reconsolidation. This consolidation-specific regulation occurs in hippocampal area CA1. Our discovery of a consolidation-specific transcription indicates that reconsolidation is only a partial recapitulation of consolidation at the transcriptional level. Such partial rather than total recapitulation may have evolved as a more economic and reliable mechanism for organisms to modify memory.

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CaMKIINalpha and CaMKIINbeta are endogenous inhibitors of the abundant synaptic protein, calcium/calmodulin-dependent protein kinase II (CaMKII). CaMKII exerts a prominent function in memory formation and the endogenous inhibitors might be important regulators of CaMKII activity during this process. Here we investigated whether or not CaMKIINalpha and CaMKIINbeta gene expressions are regulated in the mouse hippocampus and amygdala after background contextual fear conditioning. Quantitative real-time PCR revealed that the hippocampal expression of CaMKIINalpha mRNA was up-regulated 30 and 60 min after conditioning. In contrast, CaMKIINbeta mRNA expression did not change. The up-regulation of CaMKIINalpha expression was specific for the fear memory because the context alone and a shock control did not induce any variation of transcription level. Quantification of in situ hybridization signals showed that CaMKIINalpha expression increased in hippocampal area CA1, in the dentate gyrus (DG) and in the lateral amygdala (LA) 30 min after training. Our findings show an up-regulation in the expression of the endogenous inhibitor gene CaMKIINalpha during consolidation of fear memory. The early onset and the amplitude of the up-regulation are similar to those of immediate-early genes. Taken together, our results suggest that the CaMKIINalpha inhibitor has a physiological role in controlling CaMKII activity from an early stage of memory consolidation.

Autophosphorylation of the alpha-isoform of Ca2+/calmodulin-dependent kinase II switches the kinase into an autonomous activity mode. This molecular switch is important for hippocampal long-term memory formation, which requires de novo gene transcription and protein synthesis. Here, we have studied whether auto-phosphorylation of the alpha-isoform of Ca2+/calmodulin-dependent kinase II is required for gene transcription induced in the hippocampus by contextual fear conditioning. We have shown that upregulation of a nonassociative transcript, the serum and glucocorticoid-induced kinase-1 messenger RNA, is normal in alpha-isoform of Ca2+/calmodulin-dependent kinase II autophosphorylation-deficient mutant mice, whereas upregulation of an associative transcript, the nerve growth factor-inducible gene B messenger RNA, is impaired. Thus, we suggest that autophosphorylation of the alpha-isoform of Ca2+/calmodulin-dependent kinase II is a biochemical switch that regulates association-specific consolidation processes.