Date of Award
Doctor of Philosophy (PhD)
Edwin (Ted) G. Abel
Nancy M. Bonini
It is well established that cAMP signaling within neurons plays a major role in the formation of long-term memories. cAMP has three targets, protein kinase A (PKA), hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels, and exchange protein activated by cAMP (Epac). Studies have revealed that both PKA and HCN channels are important for long-term memory formation. However, little is known about the role of Epac in this process. Epac is a cAMP- dependent guanine nucleotide exchange factor for the small G proteins including Rap1.The Epac2 isoform is highly expressed in the forebrain. This dissertation examines the role of Epac in memory formation in several aspects. First, I show that activation of Epac within the hippocampus via intrahippocampal injection of Epac specific agonist 8-pCPT-2'-O-Me-cAMP was able to enhance long-term memory formation in a PKA independent fashion. Next, I show that the levels of Rap1 activity, the direct target of Epac, increased during the memory formation. Furthermore, mice injected with Epac2shRNA adeno-associated virus in the hippocampus showed decreased Epac2 protein levels and impaired memory consolidation. These results demonstrate that cAMP-Epac-Rap1 signaling plays an important role for memory consolidation, which alters prevailing assumptions that cAMP signaling modulates memory formation solely through PKA and HCN. Additionally, sleep deprivation appears to cause memory deficits by impairing cAMP signaling. Here, I show that the activity of Rap1 decreases after sleep deprivation, suggesting the memory deficits caused by sleep deprivation may be related to reductions in Epac signaling. These findings broaden our understanding of cAMP signaling in memory formation and sleep deprivation by adding Epac/Rap1 to the signaling pathways modulating memory formation.
Ma, Nan, "The Role of EPAC Signaling in Memory Consolidation and Sleep Deprivation" (2011). Publicly Accessible Penn Dissertations. 543.