〔Abstract〕 Objective To investigate the effects of embryonic inflammation on the hippocampal synaptosomal-associated protein 25(SNAP-25) level and cognitive function in middle-aged. Methods During gestational days 15-17, the CD-1 maternal mice received a daily intraperitoneal injection of lipopolysaccharides(LPS, 50 μg/kg) or the equal volume of normal saline, and the corresponding offspring were regarded as LPS group and CON group respectively. At the age of young(3-month-old) and middle-aged(15-month-old), the spatial learning and memory ability was assessed using Morris water maze(MWM), and the expression of hippocampal SNAP-25 protein was detected by immunohistochemical method and Western blot. Results Compared with the 3-month CON group, the 15-month CON group had longer swimming distance(P<0.01), lower swimming distance percentage(P<0.01) in the target quadrant, and higher hippocampal subregions(CA1, CA3, DG) SNAP-25 levels(P<0.01). The same results were obtained in 15-month LPS group compared with 15-month CON group in learning and memory phase(P<0.05), and higher hippocampal subregions(CA1, DG) SNAP-25 levels(P<0.01). Pearson correlation analysis indicated that the hippocampal CA1 and CA3 subregions SNAP-25 level was positively correlated with the swimming distance, but negatively correlated with the percentage of swimming distance in the target quadrant. Conclusion Embryonic inflammation can accelerate the impairment of spatial learning and memory and the increase of hippocampal CA1 and CA3 subregions SNAP-25 protein in middle-aged CD-1 mice, and there may be a correlation between them.