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Dictyophora duplicata is an edible fungus that contains a variety of nutrients, including polysaccharides. This study aims to investigate the monosaccharide composition and molecular weight of the Dictyophora duplicata polysaccharide (DDP-B1), followed by an exploration of its antidepressant effects in chronic unpredictable mild stress (CUMS) mice. Methods: Dictyophora duplicata was purified using a DEAE-52 column and an S-400 column to obtain DDP-B1. The monosaccharide composition and molecular weight of DDP-B1 were investigated via high-performance gel permeation chromatograph. Six-week-old C57BL\/6 male mice were utilized for the CUMS modeling to evaluate the antidepressant efficacy of DDP-B1. Fluoxetine served as the positive control group. The depressive-like behaviors and brain pathology of mice were evaluated. Immunofluorescence (IF) staining, metabolomics analysis, and western blot were employed to further investigate the underlying mechanisms. Results: DDP-B1 significantly alleviated the depression-like behavior of CUMS mice and increased the expression of SYN and PSD-95 in the mice\u2019s brains, which was further validated by western blot. Metabolomics analysis indicated a reduction in serum glutamate in CUMS mice following DDP-B1 treatment. Moreover, DDP-B1 treatment led to an increase in levels of GABAAR, BDNF, p-TrkB and p-p70S6K. Conclusions: DDP-B1 regulated abnormalities in the glutamatergic system, subsequently activated the BDNF-TrkB-mTOR pathway and mitigated the pathological manifestations of CUMS mice. This study validated the potential of DDP-B1 as an antidepressant medication and established a theoretical foundation for the development of fungi with similar properties.<\/jats:p>","DOI":"10.3390\/nu16213785","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T09:52:54Z","timestamp":1730713974000},"page":"3785","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Study on the Mechanism of Dictyophora duplicata Polysaccharide in Reducing Depression-like Behavior in Mice"],"prefix":"10.3390","volume":"16","author":[{"given":"Chenxi","family":"Yang","sequence":"first","affiliation":[{"name":"Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, School of Plant Protection, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Chen","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, School of Plant Protection, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Tang","sequence":"additional","affiliation":[{"name":"Sichuan Institute of Edible Fungi, Chendu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanzhou","family":"Li","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, School of Plant Protection, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, School of Plant Protection, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Li","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, School of Plant Protection, Jilin Agricultural University, Changchun 130118, China"},{"name":"Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China"},{"name":"National Center of Technology Innovation for Synthetic Biology, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changchun","family":"Ruan","sequence":"additional","affiliation":[{"name":"Jilin Province Technology Research Center of Biological Control Engineering, Jilin Province International Cooperation Key Laboratory for Biological Control of Agricultural Pests, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6161-0879","authenticated-orcid":false,"given":"Chunyue","family":"Wang","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, School of Plant Protection, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Xu, D., Gao, L.N., Song, X.J., Dong, Q.W., Chen, Y.B., Cui, Y.L., and Wang, Q. 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