Neurons undergo IFNγ-driven persistent epigenetic shifts and synaptopathy in encephalitis
Shammas, Ghazal; Piccinno, Margot; Egervari, Kristof; Lemeille, Sylvain; Mariotte, Alexandre; Maltese, Federica; Panzeri, Alessandra; Wagner, Ingrid; Fonta, Nicolas; Furlan, Tiphaine; Kreutzfeldt, Mario; Vincenti, Ilena; Yermanos, Alexander; Page, Nicolas; Bellone, Camilla; Muñoz, Carmen Picon; Liberto, Giovanni Di; Merkler, Doron
In infectious and autoimmune disorders of the central nervous system, neurons can become cognate immunological targets of cytotoxic T cells, leading to persistent functional and synaptic impairments. However, the molecular underpinnings of such irreversible alterations remain unclear. Using a cytotoxic T cell-driven viral encephalitis mouse model, we found synaptic loss and altered neuronal excitability that outlasted the immune response in chronically diseased mice. Employing conditional reporter mice, bulk RNA sequencing (RNA-seq), single-nucleus RNA sequencing (snRNA-seq), chromatin immunoprecipitation followed by sequencing (ChIP-seq), and assay for transposase-accessible chromatin followed by sequencing (ATAC-seq), we mapped the trajectory of transient and sustained epigenetic shifts and transcriptional changes in neurons. Notably, virus-exposed neurons, as cognate targets of cytotoxic T cells, developed interferon-gamma (IFNγ)-mediated persistent chromatin closing, reducing transcription factor accessibility and downstream synaptic gene expression. Analogous synaptic transcriptional signatures were observed in neurons of human encephalitis. Our study identifies a novel IFNγ-driven neuronal epigenetic adaptation program underlying persistent synaptopathy with implications for chronic neuroinflammatory disorders.
Highlights
• CD8+ T cell encephalitis triggers neuronal transcriptional and epigenetic shifts• Persistent chromatin inaccessibility associates with reduced synaptic gene expression
• IFNγ drives non-cytolytic viral clearance, lasting epigenetic changes, and synaptopathy
• Rasmussen patient neurons share transcriptomic changes, supporting a conserved mechanism
Web (Cell) | DOI: 10.1016/j.neuron.2025.11.006
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