AUTOIMMUNE NEUROINFLAMMATION’S FOOTPRINT ON NEURONS: A BRAIN-WIDE SIGNATURE UNVEILED

Multiple sclerosis (MS) is a chronic demyelinating disease estimated to affect 2.8 million people globally. Recent human studies indicate that MS symptoms are not merely a consequence of CNS demyelination but involve a poorly understood neuronal component. Here, we employed the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to study the neuronal response during autoimmune neuroinflammation, with a particular focus on the prodromal phase, preceding overt demyelination. We combined Targeted Recombination in Active Populations (TRAP) with brain-wide quantitative mapping, generating unprecedented neuronal activity maps at both a presymptomatic stage (day 6 post-immunization) and at the peak of disease. EAE mice exhibited a global reduction in the number of active neurons compared to controls. Notably, many of the affected regions are involved in visual processing, a system normally affected in early MS. Our findings highlight the visual cortex (VC) as a key region in early disease development. To further characterize VC deficits, we performed single-nucleus RNA sequencing and connectivity analyses. At the prodromal stage, snRNA-seq revealed transcriptional differences that suggest early synapse dysfunction in EAE. Additionally, retrograde rabies virus tracing in VC revealed a pronounced loss of connectivity at peak disease and suggested altered connectivity already at the prodromal phase. Together, our results unveiled early neuronal deficits and suggest a synaptopathy that emerge prior to immune cell infiltration and demyelination. Understanding these prodromal neuronal alterations in EAE may provide insight into MS disease progression and help identify longitudinal patterns relevant for early diagnosis and monitoring in humans.