638. MEMORY MODULATION BY DOPAMINE-CAMP SIGNAL TRANSDUCTION PATHWAYS

Abstract Background Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with traumatic memory, yet its etiology remains unclear. Reexperiencing symptoms are specific to PTSD compared to other anxiety-related disorders. Importantly, reexperiencing can be mimicked by retrieval-related events of fear memory in animal models of traumatic memory. Aims & Objectives In our previous study, we demonstrated the tight linkage between facilitated cAMP signaling and PTSD. Integrative mouse and human transcriptome analysis revealed the reduced mRNA expression of phosphodiesterase 4B (PDE4B), an enzyme that degrades cAMP, in the peripheral blood of PTSD patients showing more severe reexperiencing symptoms and the mouse hippocampus after fear memory retrieval. These findings raise the possibility that the facilitation of cAMP signaling mediating the downregulation of PDE4B expression enhances traumatic memory, thereby playing a key role in the reexperiencing symptoms of PTSD patients as a functional index of these symptoms. Therefore, we are studying the roles of cAMP signaling in memory modulation. Method Inducible transgenic dominant negative BMAL1 (dnBMAL1) expression in mouse forebrain or hippocampus disrupted retrieval of hippocampal memories at Zeitgeber Time 8-12, independently of retention delay, encoding time, and Zeitgeber entrainment cue. Results This altered retrieval profile was associated with the downregulation of hippocampal dopamine-cAMP signaling in dnBMAL1 mice. These changes included decreases in Dopamine Receptors (D1-R and D5-R) and GluA1-S845 phosphorylation by PKA. Pharmacological activation of cAMP-signals or D1/5Rs consistently rescued impaired retrieval in dnBMAL1 mice. Importantly, GluA1 S845A knock-in mice showed similar retrieval deficits with dnBMAL1 mice. Our findings suggest mechanisms underlying the regulation of retrieval by the hippocampal clock through D1/5R-cAMP-PKA-mediated GluA1 phosphorylation. Moreover, in line with these observations, pharmacological and optogenetic upregulation or downregulation of cAMP signaling transduction enhanced or impaired the retrieval and subsequent maintenance of fear memory in mice. Discussion & Conclusions These findings suggest that dopamine-cAMP signal transduction pathways positively regulate memory retrieval and maintenance (reconsolidation).