{ "abstract": "CD47, a transmembrane protein with well-established immune and neurodevelopmental roles, was recently identified as an abundant presynaptic protein in humans, non-human primates, and mice. To investigate how Cd47 influences neuronal stress and injury, we performed single-nucleus RNA sequencing of hippocampi from wild-type (WT) and Cd47 knockout (KO) mice exposed to kainic acid (KA) at convulsive (KA25; 25 mg/kg) or subconvulsive (KA3; 3 mg/kg) doses. Integrating cell-type annotations with Weighted Gene Co-expression Network Analysis (WGCNA) revealed distinct neuronal and glial gene modules whose co-expression structure differed by genotype and by KA exposure. Notably, certain modules showed KA-associated changes in co-expression structure only in Cd47-deficient cells. Enrichment analyses of these modules highlighted translational, bioenergetic, and synaptic gene sets. Comparing transcriptome-wide distributions using Wasserstein distance demonstrated that vehicle-treated KO cells most closely resembled WT cells exposed to KA3, of all fifteen pairwise comparisons. These findings suggest that Cd47 loss shifts the hippocampal transcriptome toward a state resembling mild excitotoxic stress, implicating Cd47 as a candidate regulator of neuronal stress adaptation and providing a hypothesis for testing that role. Author summary: Neurons in the brain must constantly adapt to stress, and understanding what molecular factors govern this adaptation is relevant to therapies for neurological diseases. In this study, we investigated the role of Cd47—a gene encoding a protein found abundantly at neuronal synapses—in how brain cells respond to excitotoxic injury, a form of neuronal stress implicated in epilepsy, stroke, and neurodegeneration. We performed single-nucleus RNA sequencing on hippocampal tissue from wild-type and Cd47 knockout mice exposed to subconvulsive (KA3) and convulsive (KA25) doses of kainic acid, a well-established model of excitotoxic stress. To analyze the resulting data, we applied a multi-scale computational framework combining differential gene expression analysis, gene co-expression network analysis (WGCNA), and whole-transcriptome distribution comparisons using Wasserstein distance. Our analyses revealed that removing Cd47 shifts the hippocampal transcriptome, under otherwise normal conditions, toward a state resembling subconvulsive excitotoxic stress. We also identified three genes—Fth1, Rplp1, and Apoe—as the most highly connected within the gene networks most affected by Cd47 loss, making them candidates for future functional testing. These findings are consistent with a role for Cd47 in setting the threshold at which hippocampal neurons mount a stress response; establishing that role will require direct functional testing, which this study does not provide. This work advances our understanding of neuronal vulnerability and offers a resource for research into disorders driven by excitotoxicity.", "abstract_shown": true, "affiliations": [ "Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America", "Department of Anesthesia, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, United States of America", "BIO-Centre for Computational Biology, Mines Paris, PSL Research University, Paris, France", "Institut Curie, PSL Research University, Paris, France", "INSERM, Paris, France" ], "article_type": "Research Article", "arxiv": null, "author_total": 11, "authors": [ { "affs": [ 0, 1 ], "name": "Mehrdad Kiamari", "orcid": "0009-0002-9756-3741" }, { "affs": [ 0 ], "name": "Amalia Perna" }, { "affs": [ 0 ], "name": "Matteo Santoro" }, { "affs": [ 1 ], "name": "Abdel El Ariss" }, { "affs": [ 0, 1, 2, 3, 4 ], "name": "Eloise Berson" }, { "affs": [ 0 ], "name": "Jing Zhao" }, { "affs": [ 0 ], "name": "Chandresh R. Gajera" }, { "affs": [ 0 ], "name": "Edward J. Fox" }, { "affs": [ 0 ], "name": "Kathleen S. Montine" }, { "affs": [ 1 ], "name": "Nima Aghaeepour" }, { "affs": [ 0 ], "name": "Thomas J. Montine" } ], "bibtex": "https://research.draconitic.com/paper/bqg0ywxfxxmjf.bib", "cited_by": 0, "doi": "10.1371/journal.pcbi.1014897", "fulltext_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014897", "id": "bqg0ywxfxxmjf", "issns": [ "1553-7358", "1553-734X" ], "landing_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014897", "language": "en", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Anatomy" ], [ "heading", "Animal Cells" ], [ "heading", "Apolipoprotein Genes" ], [ "heading", "Biochemistry" ], [ "heading", "Biology and Life Sciences" ], [ "heading", "Brain" ], [ "heading", "Cell Biology" ], [ "heading", "Cellular Neuroscience" ], [ "heading", "Cellular Types" ], [ "heading", "Centrality" ], [ "heading", "Computational Biology" ], [ "heading", "Computer and Information Sciences" ], [ "heading", "Gene Expression" ], [ "heading", "Gene Identification and Analysis" ], [ "heading", "Genetic Networks" ], [ "heading", "Genetics" ], [ "heading", "Genome Analysis" ], [ "heading", "Genomics" ], [ "heading", "Hippocampus" ], [ "heading", "Lipoproteins" ], [ "heading", "Medicine and Health Sciences" ], [ "heading", "Network Analysis" ], [ "heading", "Neurons" ], [ "heading", "Neuroscience" ], [ "heading", "Proteins" ], [ "heading", "Research Article" ], [ "heading", "Transcriptome Analysis" ], [ "plos", "/Biology and life sciences/Anatomy/Brain/Hippocampus" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Lipoproteins/Apolipoprotein genes" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Neurons" ], [ "plos", "/Biology and life sciences/Computational biology/Genome analysis/Transcriptome analysis" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression" ], [ "plos", "/Biology and life sciences/Genetics/Gene identification and analysis/Genetic networks" ], [ "plos", "/Biology and life sciences/Genetics/Genomics/Genome analysis/Transcriptome analysis" ], [ "plos", "/Biology and life sciences/Neuroscience/Cellular neuroscience/Neurons" ], [ "plos", "/Computer and information sciences/Network analysis" ], [ "plos", "/Computer and information sciences/Network analysis/Centrality" ], [ "plos", "/Computer and information sciences/Network analysis/Genetic networks" ], [ "plos", "/Medicine and health sciences/Anatomy/Brain/Hippocampus" ] ], "openalex": null, "pdf_url": "https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1014897&type=printable", "pmcid": "PMC13734605", "pmid": "42956090", "published": "2026-10-29", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/bqg0ywxfxxmjf.ris", "sources": [ { "first_seen": "2026-10-30T12:17:17Z", "native_id": "10.1371/journal.pcbi.1014897", "source": "plos", "url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014897" }, { "first_seen": "2026-11-08T12:24:03Z", "native_id": "PMC13734605", "source": "pmc", "url": "https://doi.org/10.1371/journal.pcbi.1014897" } ], "subjects": [ { "field": "biochemistry", "origin": "heading:Gene Expression", "subfield": "molecular-biology" }, { "field": "biology", "origin": "heading:Computational Biology", "subfield": "bioinformatics" }, { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:genetics", "subfield": "genetics-genomics" }, { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "Cd47 deficiency in mouse brain under excitotoxic stress", "title_text": "Cd47 deficiency in mouse brain under excitotoxic stress", "type": "peer-reviewed", "updated_at": "2026-11-08T12:24:03Z", "url": "https://research.draconitic.com/paper/bqg0ywxfxxmjf", "venue": "PLOS Computational Biology", "versions": [] }