{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:45:11Z","timestamp":1792176311258,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1014871","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000}}],"reference-count":90,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["7R01MH129732-04"],"award-info":[{"award-number":["7R01MH129732-04"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NARSAD","award":["27202"],"award-info":[{"award-number":["27202"]}]},{"name":"Department of Anesthesiology, University of Colorado Anschutz Medical Campus","id":[{"id":"https:\/\/ror.org\/03wmf1y16","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NeuroTechnology Center, University of Colorado Anschutz Medical Campus","id":[{"id":"https:\/\/ror.org\/03wmf1y16","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100005508","name":"Boettcher Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005508","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Genomics Research Experiences (GREU) Program"},{"name":"Data Science and Machine Learning Program, Metropolitan State University of Denver","id":[{"id":"https:\/\/ror.org\/03mnxwj46","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008116","name":"Diabetes Research Center","doi-asserted-by":"publisher","award":["P30 DK116073"],"award-info":[{"award-number":["P30 DK116073"]}],"id":[{"id":"10.13039\/100008116","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    The complement component C4 regulates synaptic refinement and plasticity in the brain and has been implicated in multiple neurological and psychiatric disorders, with especially strong genetic evidence linking elevated\n                    <jats:italic>C4A<\/jats:italic>\n                    expression to schizophrenia. However, it remains unclear whether localized C4 elevation in a small neuronal population is sufficient to reshape broader cortical gene-regulatory programs and cellular phenotypes. To address this question, we overexpressed mouse\n                    <jats:italic>C4<\/jats:italic>\n                    in approximately 2% of prefrontal cortical neurons using in utero electroporation and performed bulk RNA sequencing on microdissected prefrontal cortex. Despite the sparse manipulation, C4-OE was associated with broad transcriptional remodeling across tissue composed predominantly of untransfected cells, including coordinated changes in cholesterol biosynthesis, axon- and synaptic-associated programs, vascular\/ECM pathways, and immune- and stress-related responses. Comparison with a schizophrenia synaptic proteomic dataset identified limited global correspondence but selective gene- and pathway-level overlap in specific molecular programs. Reference-based projection of directional DEG signatures onto a cortical single-cell transcriptomic reference further identified cell-type-associated structure, including prominent astrocyte- and vascular-associated axes and distinct lipid\/metabolic, vascular\/endothelial\u2013interferon-associated, and immune\/stress correlation domains. Spatial validation with MFISH showed increased\n                    <jats:italic>Hmgcr<\/jats:italic>\n                    expression in neighboring GFP-negative cells, while PLIN2 imaging revealed increased DAPI-associated\/perinuclear lipid-droplet burden within the local C4-OE field. Together, these findings support a model in which sparse neuronal C4 elevation is associated with broader remodeling of the local cortical environment, including a non-cell-autonomous component involving neighboring-cell lipid-associated responses. These results expand the interpretation of C4 risk biology beyond synapse elimination alone and suggest that focal immune-gene dysregulation can engage lipid-homeostatic, stress-related, and cell-type-associated transcriptional programs relevant to cortical circuit vulnerability.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014871","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:31:51Z","timestamp":1791826311000},"page":"e1014871","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sparse neuronal C4 elevation induces network-wide transcriptomic and lipid-droplet remodeling in the cortical microenvironment"],"prefix":"10.1371","volume":"22","author":[{"given":"Marta","family":"S\u00e1nchez-Carbonell","sequence":"first","affiliation":[{"name":"University of Colorado Anschutz Medical Campus","place":["Aurora, Colorado, United States of 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Engineering"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clay","family":"Griffin-Derr","sequence":"additional","affiliation":[{"name":"Metropolitan State University of Denver","place":["Denver, Colorado, United States of America"],"department":["Data Science and Machine Learning Program, Department of Computer Sciences"]},{"name":"Metropolitan State University of Denver","place":["Denver, Colorado, United States of America"],"department":["Genomics Research Experiences for Undergraduates (GREU) Program, Center for Advanced STEM Education (CASE)"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik G.","family":"Stich","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus","place":["Aurora, Colorado, United States of America"],"department":["NeuroTechnology Center"]},{"name":"University of Colorado Anschutz Medical Campus","place":["Aurora, Colorado, United States of America"],"department":["Advanced Light Microscopy Core, NeuroTechnology Center"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia V.","family":"Cieslewicz","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus","place":["Aurora, Colorado, United States of America"],"department":["Department of Anesthesiology"]},{"name":"University of Colorado Anschutz Medical Campus","place":["Aurora, Colorado, United States of America"],"department":["NeuroTechnology Center"]},{"name":"Quantitative Biosciences and Engineering, Colorado School of Mines","place":["Golden, Colorado, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheyla Esther","family":"Carmen Sifuentes","sequence":"additional","affiliation":[{"name":"Escuela de Gen\u00e9tica y Biotecnolog\u00eda, Universidad Nacional Mayor de San Marcos","place":["Lima, Peru"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhushikesh 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