Recall and reconsolidation of contextual fear memory: differential control by ERK and Zif268 expression dosage

Compelling evidence points to the existence of independent cellular processes involved in the consolidation and reconsolidation of memory. For instance, a double dissociation has been reported between hippocampal Extracellular-Regulated Kinase-1/2 (ERK1/2) activity being necessary for contextual fear conditioning (CFC) consolidation but not reconsolidation. Conversely, hippocampal expression of the immediate early gene Zif268 is necessary for CFC reconsolidation but not consolidation. Since we previously reported that ERK1/2 controls the transcription of Zif268 in the hippocampus, we examined the precise role of ERK1/2 activity and Zif268 gene expression dosage in CFC memory processing. For this, we first assessed performance of Zif268 homozygous and heterozygous mutant mice in a CFC paradigm. Whereas Zif268-/- mice displayed a deficit of both consolidation and reconsolidation, Zif268+/- mice displayed a selective deficit of reconsolidation only, therefore pointing to the relationship between Zif268 gene expression dosage and CFC memory processing. Zif268 gene expression dosage interfered with the reconsolidation process if and only if CFC memory was relatively recently encoded and directly reactivated. Furthermore, CFC memory strengthening previously reported to involve Zif268 expression in the hippocampus was spared in Zif268+/- mice. Finally, blocking ERK1/2 activity prior to CFC retrieval prevented the deficit of reconsolidation observed in Zif268+/- mice. Collectively, these results highlight a tight relationship between Zif268 gene expression dosage and CFC memory processing. They also suggest that ERK1/2 activity upon CFC memory recall is necessary for its retrieval, a prerequisite for its reactivation and subsequent reconsolidation.