Journal of affective disorders · 2026
PDE2A is involved in negative emotional behaviors via the cAMP-PKA signaling pathway in the SPS&S model.
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Jiang Baoying, Wu Lanxia, Zhang Guohui, Fu Yuzi, Lu Yining, Wei Peili, Lin Han, Zhu Guohui, Nie Jiwei, Sun Lin
Аннотация
BACKGROUND: Post-traumatic stress disorder (PTSD) is characterized by negative affective symptoms, including anxiety, depression, anhedonia, and fear. The molecular mechanisms underlying these symptoms remain poorly understood. Phosphodiesterase 2A (PDE2A), a regulator of cyclic adenosine monophosphate (cAMP) signaling, has been implicated in neuropsychiatric disorders.
OBJECTIVE: This study aimed to investigate the role of the PDE2A-cAMP-protein kinase A (PKA) signaling pathway in negative emotional behaviors induced by traumatic stress.
METHODS: Transcriptomic datasets were analyzed to identify differentially expressed genes and enriched pathways. A rat PTSD model was established using single prolonged stress combined with foot shocks (SPS&S). Behavioral tests were performed, and PDE2A-cAMP-PKA signaling alterations in the amygdala were examined. The effects of PDE2A inhibitor Hcyb1 and the PKA inhibitor H89 were evaluated.
RESULTS: Bioinformatics analysis identified PDE2A as a hub gene associated with PTSD, with significant enrichment of the cAMP signaling pathway. SPS&S rats exhibited anxiety-, depression-like behaviors, and anhedonia, accompanied by increased PDE2A expression and reduced cAMP and phosphorylated PKA (p-PKA) levels in the amygdala. Hcyb1 treatment alleviated behavioral deficits, decreased PDE2A expression, and restored cAMP and p-PKA signaling. H89 blocked p-PKA activation and partially reversed the behavioral benefits of Hcyb1.
CONCLUSION: These findings suggest that amygdala PDE2A-cAMP-PKA signaling is associated with negative emotional behaviors in the SPS&S model. PDE2A inhibition may ameliorate behavioral deficits through PKA-related signaling. However, the peripheral blood transcriptomic data, lack of direct PDE2A activity and cAMP/cGMP measurements, and limited biochemical validation constrain mechanistic interpretation. Further studies using brain-derived datasets and comprehensive biochemical approaches are warranted.
OBJECTIVE: This study aimed to investigate the role of the PDE2A-cAMP-protein kinase A (PKA) signaling pathway in negative emotional behaviors induced by traumatic stress.
METHODS: Transcriptomic datasets were analyzed to identify differentially expressed genes and enriched pathways. A rat PTSD model was established using single prolonged stress combined with foot shocks (SPS&S). Behavioral tests were performed, and PDE2A-cAMP-PKA signaling alterations in the amygdala were examined. The effects of PDE2A inhibitor Hcyb1 and the PKA inhibitor H89 were evaluated.
RESULTS: Bioinformatics analysis identified PDE2A as a hub gene associated with PTSD, with significant enrichment of the cAMP signaling pathway. SPS&S rats exhibited anxiety-, depression-like behaviors, and anhedonia, accompanied by increased PDE2A expression and reduced cAMP and phosphorylated PKA (p-PKA) levels in the amygdala. Hcyb1 treatment alleviated behavioral deficits, decreased PDE2A expression, and restored cAMP and p-PKA signaling. H89 blocked p-PKA activation and partially reversed the behavioral benefits of Hcyb1.
CONCLUSION: These findings suggest that amygdala PDE2A-cAMP-PKA signaling is associated with negative emotional behaviors in the SPS&S model. PDE2A inhibition may ameliorate behavioral deficits through PKA-related signaling. However, the peripheral blood transcriptomic data, lack of direct PDE2A activity and cAMP/cGMP measurements, and limited biochemical validation constrain mechanistic interpretation. Further studies using brain-derived datasets and comprehensive biochemical approaches are warranted.