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Recent clinical studies revealed increased blood\u2013brain barrier (BBB) permeability in mTBI patients, which correlated with secondary damage after mTBI. However, the cascade of cellular events initiated by exposure to blood-borne factors resulting in sustained damage is not fully understood. We previously reported that astrocytes respond atypically to mTBI, rapidly losing many proteins essential to their homeostatic function, while classic scar formation does not occur. Here, we tested the hypothesis that mTBI-induced BBB damage causes atypical astrocytes through exposure to blood-borne factors. Using an mTBI mouse model, two-photon imaging, an endothelial cell-specific genetic ablation approach, and serum-free primary astrocyte cultures, we demonstrated that areas with atypical astrocytes coincide with BBB damage and that exposure of astrocytes to plasma proteins is sufficient to initiate loss of astrocyte homeostatic proteins. Although mTBI resulted in frequent impairment of both physical and metabolic BBB properties and leakage of small-sized blood-borne factors, deposition of the coagulation factor fibrinogen or vessel rupture were rare. Surprisingly, even months after mTBI, BBB repair did not occur in areas with atypical astrocytes. Together, these findings implicate that even relatively small BBB disturbances are sustained long term, and render nearby astrocytes dysfunctional, likely at the cost of neuronal health and function.<\/jats:p>","DOI":"10.1089\/neu.2021.0204","type":"journal-article","created":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T05:30:04Z","timestamp":1637559004000},"page":"211-226","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":61,"title":["Mild Traumatic Brain Injury\/Concussion Initiates an Atypical Astrocyte Response Caused by Blood\u2013Brain Barrier Dysfunction"],"prefix":"10.1177","volume":"39","author":[{"given":"Kijana K.","family":"George","sequence":"first","affiliation":[{"name":"Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia, USA."},{"name":"Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Roanoke, Virginia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin P.","family":"Heithoff","sequence":"additional","affiliation":[{"name":"Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia, USA."},{"name":"Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleksii","family":"Shandra","sequence":"additional","affiliation":[{"name":"Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia, USA."},{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Robel","sequence":"additional","affiliation":[{"name":"Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia, USA."},{"name":"Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, USA."},{"name":"Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"e_1_3_7_2_2","doi-asserted-by":"publisher","DOI":"10.1080\/16501960410023732"},{"key":"e_1_3_7_3_2","doi-asserted-by":"publisher","DOI":"10.1177\/0963689717714092"},{"key":"e_1_3_7_4_2","doi-asserted-by":"publisher","DOI":"10.1177\/0963689717714092"},{"key":"e_1_3_7_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11940-006-0031-9"},{"key":"e_1_3_7_6_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2018.6096"},{"key":"e_1_3_7_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.01115"},{"key":"e_1_3_7_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.00203"},{"key":"e_1_3_7_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws322"},{"key":"e_1_3_7_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2016.09.049"},{"key":"e_1_3_7_11_2","doi-asserted-by":"crossref","unstructured":"Sahyouni R. 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(1990). Brain-type glucose transporter (GLUT-1) is selectively localized to the blood\u2013brain barrier. Studies with quantitative western blotting and in situ hybridization. J. Biol. Chem. 265, 18, 035\u201318,040.","journal-title":"Studies with quantitative western blotting and in situ hybridization. J. Biol. Chem"},{"key":"e_1_3_7_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/gene.20162"},{"key":"e_1_3_7_26_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44667"},{"key":"e_1_3_7_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80781-3"},{"key":"e_1_3_7_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.116.013805"},{"key":"e_1_3_7_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.10032"},{"key":"e_1_3_7_30_2","doi-asserted-by":"crossref","unstructured":"Frik J. Merl-Pham J. Plesnila N. Mattugini N. Kjell J. Kraska J. G\u00f3mez R.M. Hauck S.M. Sirko S. and G\u00f6tz M. (2018). 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