Metabolic neuronal alterations are hallmark features of various chronic inflammatory diseases of the central nervous system (CNS). Notably, mitochondrial dysfunction and subsequent energy failure are widely hypothesized to be a central mechanism underlying long-term neuronal damage in inflammatory CNS diseases. However, the mechanisms by which immune cells disrupt neuronal metabolic function and how these contribute to neuronal damage remain poorly understood.

In this thesis, we harnessed the “viral déjà-vu” murine model of CD8+ T cell-mediated encephalitis to investigate the short- and long-term metabolic alterations in neurons following CD8+ T cell engagement. My research demonstrates that neurons experience durable synaptic loss, persisting even after the contraction of the CD8+ T cells brain infiltration. These structural alterations are associated with enduring neuronal metabolic modifications, including disrupted protein synthesis and mitochondrial dysfunction characterized by impaired oxidative phosphorylation.

These neuronal metabolic alterations are partly driven by the activation of the neuronal interferon-γ-receptor (IFNGR) in response to interferon-γ (IFN-γ) produced by CD8+ T cells. This provides valuable insight into the long-term modulation of neuronal metabolism by pro- inflammatory cytokines. Among the neuronal signaling pathways activated by IFN-γ, this study highlights the role of the Immune-Responsive Gene 1 (IRG1), which leads to the production of itaconate, a well-known metabolic inhibitor, in the context of viral déjà-vu disease. We propose itaconate as a potential candidate responsible for the observed metabolic impairment and clinical symptoms of the disease.

These findings delineate the impact of T-cell-mediated inflammation on neuronal metabolism and shed light on eventual metabolic mechanisms driving synaptopathy. In conclusion, this comprehensive study advances our understanding of the metabolic underpinnings of neuroinflammation-induced long-lasting synaptic pathology.