Encephalitis, defined as the inflammation of brain parenchyma, can be triggered by various etiologies, including infections or autoimmune reactions. When long-lived post-mitotic neurons are infected, the resulting immune response may tailor a non-cytolytic viral clearance mechanism to prevent an irreversible loss of these vital cells. Nevertheless, such an immune attack against neurons can lead to permanent neurological deficits. How immune cell-neuron interactions perpetuate detrimental long-lasting neuronal dysfunction is still poorly understood. In this thesis, we harnessed the viral déjà vu model to investigate the outcomes of a T cell-mediated attack on neuronal structure and network integrity. We demonstrated that non-cytolytic viral clearance triggers enduring damage to synaptic connections. We also validated that synaptic pathology is associated with long-term deterioration of electrophysiological functions affecting neuronal intrinsic excitability. We profiled the temporal transcriptional patterns and epigenetic landscapes in neurons throughout the course of encephalitis disease. Through bulk and single nuclear RNA sequencing (RNAseq) studies, we uncovered a unique neuronal inflammatory signature and gene regulatory networks (GRN) emerging under T cell-induced encephalitis and further corroborated our findings in human hippocampus samples of a patient suffering from Rasmussen’s Encephalitis (RE). We applied chromatin immunoprecipitation (ChIP) and assay of transposase-accessible chromatin (ATAC) followed by sequencing to discern neuronal chromatin accessibility and chromatin states in the disease. These analyses showed that neurons undergo long-lasting epigenetic remodeling involving the deposition of histone marks and changes in chromatin accessibility. These neuronal adaptations associated with synaptic pathology were the consequence of an inflammatory process mediated by CD8⁺ T cells and persisted after the immune process had receded. We further inferred chromatin accessibility with gene expression patterns and identified distinct Epigenetic-Transcriptional Response (ETR) profiles. These profiles range from transient to sustained changes, with notable variations between virus-exposed and bystander neuronal populations. Furthermore, our analysis uncovered epigenetic priming that guides enduring transcriptional alterations anchored with long-term synaptic pathology in virus-exposed neurons, underscoring the outcomes of direct T cell engagement. Such neurons exhibited pronounced susceptibility to synaptic loss, a critical factor contributing to the lingering neurological deficits observed in neuroinflammatory diseases. These findings disentangle the impact of T cell-mediated inflammation on synaptic integrity and shed light on molecular mechanisms driving these structural and functional neuronal changes. In conclusion, this comprehensive study advances our understanding of the molecular underpinnings of neuroinflammation-induced long-lasting synaptic pathology.