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.