Temporal and Regional Regulation of Gene Expression by Calcium-Stimulated Adenylyl Cyclase Activity during Fear Memory

Background: The Ca2+-stimulated adenylyl cyclases (ACs), AC1 and AC8, are key components of long-term memory processing. AC1 and AC8 double knockout mice (Adcy1(-/-) Adcy8(-/-); DKO) display impaired fear memory processing; the mechanism of this impairment is largely unknown. Methodology/Principal Findings: We hypothesize that the Ca2+-stimulated ACs modulate long-lasting transcriptional changes essential for fear memory consolidation and maintenance. Here, we report a genome-wide study of gene expression changes associated with conditioned fear (CF) memory in wild-type and DKO mice to identify AC-dependent gene regulatory changes that occur in the amygdala and hippocampus at baseline and different time points after CF learning. We observed an overall decrease in transcriptional changes in DKO mice across all time points, but most strikingly, at periods when memory consolidation and retention should be occurring. Further, we identified a shared set of transcription factor binding sites in genes upregulated in wild-type mice that were associated with downregulated genes in DKO mice. To prove the temporal and regional importance of AC activity on different stages of memory processing, the tetracycline-off system was used to produce mice with forebrain-specific inducible expression of AC8 on a DKO background. CF behavioral results reveal that adult restoration of AC8 activity in the forebrain is sufficient for intact learning, while cessation of this expression at any time point across learning causes memory deficits. Conclusions/Significance: Overall, these studies demonstrate that the Ca2+-stimulated ACs contribute to the formation and maintenance of fear memory by a network of long-term transcriptional changes.