PGE2‐EP3 signaling exacerbates hippocampus‐dependent cognitive impairment after laparotomy by reducing expression levels of hippocampal synaptic plasticity‐related proteins in aged mice

Summary Aim Multifactors contribute to the development of postoperative cognitive dysfunction ( POCD ), of which the most important mechanism is neuroinflammation. Prostaglandin E2 ( PGE 2) is a key neuroinflammatory molecule and could modulate hippocampal synaptic transmission and plasticity. This study was designed to investigate whether PGE 2 and its receptors signaling pathway were involved in the pathophysiology of POCD . Methods Sixteen‐month old male C57 BL /6J mice were exposed to laparotomy. Cognitive function was evaluated by fear conditioning test. The levels of PGE 2 and its 4 distinct receptors ( EP 1‐4) were assessed by biochemical analysis. Pharmacological or genetic methods were further applied to investigate the role of the specific PGE 2 receptors. Results Here, we found that the transcription and translation level of the EP 3 receptor in hippocampus increased remarkably, but not EP 1, EP 2, or EP 4. Immunofluorescence results showed EP 3 positive cells in the hippocampal CA 1 region were mainly neurons. Furthermore, pharmacological blocking or genetic suppression of EP 3 could alleviate surgery‐induced hippocampus‐dependent memory deficits and rescued the expression of plasticity‐related proteins, including cAMP response element‐binding protein ( CREB ), activity‐regulated cytoskeletal‐associated protein (Arc), and brain‐derived neurotrophic factor ( BDNF ) in hippocampus. Conclusion This study showed that PGE 2‐ EP 3 signaling pathway was involved in the progression of POCD and identified EP 3 receptor as a promising treatment target.