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Adv."],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:p>\n                    The ventral hippocampus plays a crucial role in regulating emotional and motivated behaviors. However, the molecular mechanisms underlying its dysfunction in major depressive disorder (MDD) remain poorly understood. Here, we identified elevated expression of vitamin D binding protein (VDBP) in the hippocampi of chronic unpredictable mild stress (CUMS)\u2013susceptible mice, which correlated with the severity of depression-like behaviors. Notably, VDBP up-regulation was specifically in ventral CA3 excitatory (vCA3\n                    <jats:sup>CaMKII\u03b1<\/jats:sup>\n                    ) neurons. CA3\n                    <jats:sup>CaMKII\u03b1<\/jats:sup>\n                    VDBP overexpression led to inhibited neuronal activity, synaptic and dendritic impairments, and, ultimately, depression-like behaviors. Conversely, vCA3\n                    <jats:sup>CaMKII\u03b1<\/jats:sup>\n                    -specific VDBP knockdown enhanced resilience to chronic stress. Mechanistically, VDBP directly interacted with PIK3R3 to inhibit the PI3K-Akt-mTOR pathway in a cell-autonomous manner, leading to excessive autophagy and subsequent neuronal dysfunction. Chemogenetic activation, intervention using the Akt-specific activator SC79, and site-specific mutation disrupting the VDBP-PIK3R3 interaction ameliorated vCA3\n                    <jats:sup>CaMKII\u03b1<\/jats:sup>\n                    VDBP-induced depression-like phenotypes. Collectively, these findings underscore the critical involvement of vCA3\n                    <jats:sup>CaMKII\u03b1<\/jats:sup>\n                    neuron\u2013derived VDBP in stress-induced depressive pathology and highlight its potential as a therapeutic target for MDD.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh9563","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:59:24Z","timestamp":1792000764000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Vitamin D binding protein in ventral CA3 of the hippocampus drives stress-induced depression"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2621-4730","authenticated-orcid":true,"given":"Yan","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, Jiangsu, China."},{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuiju","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5480-0888","authenticated-orcid":true,"given":"Zhijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, Jiangsu, China."},{"name":"Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(21)00395-3"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2025.120299"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww083"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-60774-6"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1176\/jnp.7.1.103"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.11.031"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0241-y"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23260-3"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.61718"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1115396109"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1017\/neu.2017.16"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2017.05.013"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2018.02.011"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1210\/edrv-10-3-294"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1159\/000492497"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0447.1977.tb00146.x"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-05873-6"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2020.08.078"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202410273"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)38107-9"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840210628"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.06.016"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2020.11.018"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107300"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202254911"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adn4556"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-100818-125242"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.01.019"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08807-4"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-023-2510-0"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/pr8001645"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1063(1998)8:6<608::AID-HIPO3>3.0.CO;2-7"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2025.111848"},{"key":"e_1_3_2_35_2","first-page":"1","article-title":"Vitamin 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