{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:49:33Z","timestamp":1787237373246,"version":"build-2736575974"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Complement C3 plays important roles in neuroinflammation and is significantly upregulated in hippocampal tissues from patients with mesial temporal lobe epilepsy (mTLE) that is characterized by neuronal loss and gliosis. However, the temporal and spatial expression of complement C3 in the epileptic brain remain unclear. In this study, we first confirmed the upregulation of C3 in resected hippocampal tissues encompassing the CA1\u2013CA4 regions from patients with mTLE with hippocampal sclerosis (mTLE-HS) using RNA sequencing, and in an mTLE mouse model using microarray data from the GEO database. Using a novel floxed C3-IRES-Tdtomato knock-in mouse line, we identified sustained C3 overexpression mainly in reactive astrocytes within the hippocampal stratum lacunosum-moleculare. This activation emerged 3\u202fdays after pilocarpine-induced status epilepticus, progressively extended to the CA1 region by 3\u202fweeks, and highlighted region- and stage-specific dysregulation of C3 during epileptogenesis.<\/jats:p>","DOI":"10.3389\/fneur.2025.1682488","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T05:18:10Z","timestamp":1763529490000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Dynamic astrocytic complement C3 activation in the epileptic hippocampus"],"prefix":"10.3389","volume":"16","author":[{"given":"Mi","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Romagnolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Aronica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/S0002-9440(10)64753-0","article-title":"Temporal accrual of complement proteins in amyloid plaques in down's syndrome with Alzheimer's disease","volume":"156","author":"Stoltzner","year":"2000","journal-title":"Am J Pathol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1097\/01.wad.0000165506.60370.94","article-title":"Complement activation in very early Alzheimer disease","volume":"19","author":"Zanjani","year":"2005","journal-title":"Alzheimer Dis Assoc Disord"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1186\/s12974-023-02850-6","article-title":"Alzheimer's disease-associated complement gene variants influence plasma complement protein levels","volume":"20","author":"Veteleanu","year":"2023","journal-title":"J Neuroinflammation"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.nbd.2011.01.002","article-title":"Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation","volume":"42","author":"Sta","year":"2011","journal-title":"Neurobiol Dis"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.nbd.2007.01.015","article-title":"Complement activation in experimental and human temporal lobe epilepsy","volume":"26","author":"Aronica","year":"2007","journal-title":"Neurobiol Dis"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.expneurol.2017.06.009","article-title":"Enhanced classical complement pathway activation and altered phagocytosis signaling molecules in human epilepsy","volume":"295","author":"Wyatt","year":"2017","journal-title":"Exp Neurol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.eplepsyres.2007.10.002","article-title":"Inflammatory processes in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex","volume":"78","author":"Boer","year":"2008","journal-title":"Epilepsy Res"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1002\/ana.21524","article-title":"Immunoglobulins and complement in postmortem multiple sclerosis tissue","volume":"65","author":"Barnett","year":"2009","journal-title":"Ann Neurol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/2051-5960-2-53","article-title":"Complement activation in multiple sclerosis plaques: an immunohistochemical analysis","volume":"2","author":"Ingram","year":"2014","journal-title":"Acta Neuropathol Commun"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S0165-5728(96)00164-6","article-title":"Elevated levels of the complement components C3 and factor B in ventricular cerebrospinal fluid of patients with traumatic brain injury","volume":"73","author":"Kossmann","year":"1997","journal-title":"J Neuroimmunol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1089\/089771501316919139","article-title":"Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) correlate with blood-brain barrier dysfunction in patients with traumatic brain injury","volume":"18","author":"Stahel","year":"2001","journal-title":"J Neurotrauma"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/nature16549","article-title":"Schizophrenia risk from complex variation of complement component 4","volume":"530","author":"Sekar","year":"2016","journal-title":"Nature"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"6427","DOI":"10.1038\/s41467-022-33797-6","article-title":"Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia","volume":"13","author":"Gracias","year":"2022","journal-title":"Nat Commun"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.bbi.2025.03.009","article-title":"Assessment of complement cascade components in patients with major depressive disorder","volume":"127","author":"Quintanilla","year":"2025","journal-title":"Brain Behav Immun"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1038\/s41593-018-0334-7","article-title":"Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning","volume":"22","author":"Sellgren","year":"2019","journal-title":"Nat Neurosci"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.bbi.2022.12.019","article-title":"Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice","volume":"109","author":"Wang","year":"2023","journal-title":"Brain Behav Immun"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"16879","DOI":"10.1073\/pnas.0406678101","article-title":"Activation of the complement system generates antibacterial peptides","volume":"101","author":"Nordahl","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/nri2231","article-title":"Complement driven by conformational changes","volume":"8","author":"Gros","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1038\/nri2620","article-title":"Complement regulators and inhibitory proteins","volume":"9","author":"Zipfel","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"6391","DOI":"10.1523\/JNEUROSCI.6221-11.2012","article-title":"Genomic analysis of reactive astrogliosis","volume":"32","author":"Zamanian","year":"2012","journal-title":"J Neurosci Off J Soc Neurosci"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1038\/s41593-025-01979-2","article-title":"GABA-dependent microglial elimination of inhibitory synapses underlies neuronal hyperexcitability in epilepsy","volume":"28","author":"Chen","year":"2025","journal-title":"Nat Neurosci"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/s41586-021-03892-7","article-title":"A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis","volume":"597","author":"Absinta","year":"2021","journal-title":"Nature"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.immuni.2019.12.004","article-title":"Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease","volume":"52","author":"Werneburg","year":"2020","journal-title":"Immunity"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1126\/science.aad8373","article-title":"Complement and microglia mediate early synapse loss in Alzheimer mouse models","volume":"352","author":"Hong","year":"2016","journal-title":"Science"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"eaal3222","DOI":"10.1126\/science.aal3222","article-title":"An environment-dependent transcriptional network specifies human microglia identity","volume":"356","author":"Gosselin","year":"2017","journal-title":"Science"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1038\/s41586-019-0924-x","article-title":"Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution","volume":"566","author":"Masuda","year":"2019","journal-title":"Nature"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.immuni.2017.08.008","article-title":"The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases","volume":"47","author":"Krasemann","year":"2017","journal-title":"Immunity"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.1038\/s41593-019-0532-y","article-title":"Mapping microglia states in the human brain through the integration of high-dimensional techniques","volume":"22","author":"Sankowski","year":"2019","journal-title":"Nat Neurosci"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1093\/brain\/awl001","article-title":"Large-scale expression study of human mesial temporal lobe epilepsy: evidence for dysregulation of the neurotransmission and complement systems in the entorhinal cortex","volume":"129","author":"Jamali","year":"2006","journal-title":"Brain"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.nbd.2017.10.012","article-title":"Status epilepticus triggers long-lasting activation of complement C1q-C3 signaling in the hippocampus that correlates with seizure frequency in experimental epilepsy","volume":"109","author":"Schartz","year":"2018","journal-title":"Neurobiol Dis"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1177\/1535759719890336","article-title":"Emerging roles for microglial phagocytic signaling in epilepsy","volume":"20","author":"Wyatt-Johnson","year":"2020","journal-title":"Epilepsy Curr"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1007\/s00429-013-0528-4","article-title":"MRI changes and complement activation correlate with epileptogenicity in a mouse model of temporal lobe epilepsy","volume":"219","author":"Kharatishvili","year":"2014","journal-title":"Brain Struct Funct"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1002\/glia.23955","article-title":"The complement C3-C3aR pathway mediates microglia-astrocyte interaction following status epilepticus","volume":"69","author":"Wei","year":"2021","journal-title":"Glia"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"2170","DOI":"10.3390\/jcm8122170","article-title":"Synaptic pruning by microglia in epilepsy","volume":"8","author":"Andoh","year":"2019","journal-title":"J Clin Med"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1265944","DOI":"10.3389\/fnmol.2023.1265944","article-title":"Mice deficient in complement C3 are protected against recognition memory deficits and astrogliosis induced by status epilepticus","volume":"16","author":"Schartz","year":"2023","journal-title":"Front Mol Neurosci"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1186\/s12974-022-02587-8","article-title":"Captopril alleviates epilepsy and cognitive impairment by attenuation of C3-mediated inflammation and synaptic phagocytosis","volume":"19","author":"Dong","year":"2022","journal-title":"J Neuroinflammation"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.jneumeth.2008.04.019","article-title":"The pilocarpine model of temporal lobe epilepsy","volume":"172","author":"Curia","year":"2008","journal-title":"J Neurosci Methods"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"2180","DOI":"10.1038\/s41467-024-46592-2","article-title":"Identification of gene regulatory networks affected across drug-resistant epilepsies","volume":"15","author":"Francois","year":"2024","journal-title":"Nat Commun"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"ref42","first-page":"281","article-title":"Modification of seizure activity by electrical stimulation. Part II. Motor seizure","volume-title":"Electroencephalogr Clin Neurophysiol","author":"Racine","year":"1972"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1111\/epi.16868","article-title":"Defining the latent period of epileptogenesis and epileptogenic zone in a focal cortical dysplasia type II (FCDII) rat model","volume":"62","author":"Kao","year":"2021","journal-title":"Epilepsia"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1002\/cne.901670303","article-title":"Topographic organization of the projections from the entorhinal area to the hippocampal formation of the rat","volume":"167","author":"Steward","year":"1976","journal-title":"J Comp Neurol"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1002\/cne.901690306","article-title":"Cells of origin of entorhinal cortical afferents to the hippocampus and fascia dentata of the rat","volume":"169","author":"Steward","year":"1976","journal-title":"J Comp Neurol"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1002\/(SICI)1098-1063(1996)6:4<347::AID-HIPO1>3.0.CO;2-I","article-title":"Interneurons of the hippocampus","volume":"6","author":"Freund","year":"1996","journal-title":"Hippocampus"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"2348","DOI":"10.1093\/cercor\/bhw093","article-title":"Synaptic remodeling of entorhinal input contributes to an aberrant hippocampal network in temporal lobe epilepsy","volume":"27","author":"Janz","year":"2017","journal-title":"Cereb Cortex"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1007\/s12264-021-00750-4","article-title":"Complement C3 aggravates post-epileptic neuronal injury via activation of TRPV1","volume":"37","author":"Jiang","year":"2021","journal-title":"Neurosci Bull"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1146\/annurev-neuro-112723-035356","article-title":"Astrocytes as key regulators of neural signaling in health and disease","volume":"48","author":"Won","year":"2025","journal-title":"Annu Rev Neurosci"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1223891","DOI":"10.3389\/fncir.2023.1223891","article-title":"Local and long-range GABAergic circuits in hippocampal area CA1 and their link to Alzheimer's disease","volume":"17","author":"Hern\u00e1ndez-Frausto","year":"2023","journal-title":"Front Neural Circuits"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1038\/nn.3235","article-title":"OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons","volume":"15","author":"Le\u00e3o","year":"2012","journal-title":"Nat Neurosci"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1682488\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T05:18:11Z","timestamp":1763529491000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1682488\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":51,"alternative-id":["10.3389\/fneur.2025.1682488"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2025.1682488","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]},"article-number":"1682488"}}