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Peer-reviewedCC BY 4.0PLOS Computational Biology

Cd47 deficiency in mouse brain under excitotoxic stress

  • Mehrdad Kiamari1,2
  • Amalia Perna1
  • Matteo Santoro1
  • Abdel El Ariss2
  • Eloise Berson1,2,3,4,5
  • Jing Zhao1
  • Chandresh R. Gajera1
  • Edward J. Fox1
  • Kathleen S. Montine1
  • Nima Aghaeepour2
  • Thomas J. Montine1
5 affiliations
  1. 1Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America
  2. 2Department of Anesthesia, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, United States of America
  3. 3BIO-Centre for Computational Biology, Mines Paris, PSL Research University, Paris, France
  4. 4Institut Curie, PSL Research University, Paris, France
  5. 5INSERM, Paris, France
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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.

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Cite

BibTeXRIS
BibTeX
@article{kiamari2026cd47,
  title = {{Cd47 deficiency in mouse brain under excitotoxic stress}},
  author = {Mehrdad Kiamari and Amalia Perna and Matteo Santoro and Abdel El Ariss and Eloise Berson and Jing Zhao and Chandresh R. Gajera and Edward J. Fox and Kathleen S. Montine and Nima Aghaeepour and Thomas J. Montine},
  journal = {PLOS Computational Biology},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pcbi.1014897},
  url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014897},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Cd47 deficiency in mouse brain under excitotoxic stress
AU  - Mehrdad Kiamari
AU  - Amalia Perna
AU  - Matteo Santoro
AU  - Abdel El Ariss
AU  - Eloise Berson
AU  - Jing Zhao
AU  - Chandresh R. Gajera
AU  - Edward J. Fox
AU  - Kathleen S. Montine
AU  - Nima Aghaeepour
AU  - Thomas J. Montine
PY  - 2026
DA  - 2026/10/29
JO  - PLOS Computational Biology
DO  - 10.1371/journal.pcbi.1014897
UR  - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014897
AB  - 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.
SN  - 1553-7358
SN  - 1553-734X
ER  -