Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis

TLDR

Neurodegeneration is an irreversible pathological event that occurs during chronic inflammatory diseases of the CNS. In EAE, myelin‑specific immune cells invade the CNS, downregulate Arc/Arg3.1, and cause abnormal AMPA receptor expression and phosphorylation, driving neurodegeneration. Inflammation in EAE increases glutamate transmission, induces early synaptic degeneration and dendritic spine loss independent of demyelination, is linked to microglial TNF‑α release, and can be mitigated by AMPA receptor blockade, underscoring the need for early neuroprotective therapies.

Abstract

Neurodegeneration is the irremediable pathological event occurring during chronic inflammatory diseases of the CNS. Here we show that, in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, inflammation is capable in enhancing glutamate transmission in the striatum and in promoting synaptic degeneration and dendritic spine loss. These alterations occur early in the disease course, are independent of demyelination, and are strongly associated with massive release of tumor necrosis factor-α from activated microglia. CNS invasion by myelin-specific blood-borne immune cells is the triggering event, and the downregulation of the early gene Arc/Arg3.1 , leading to the abnormal expression and phosphorylation of AMPA receptors, represents a culminating step in this cascade of neurodegenerative events. Accordingly, EAE-induced synaptopathy subsided during pharmacological blockade of AMPA receptors. Our data establish a link between neuroinflammation and synaptic degeneration and calls for early neuroprotective therapies in chronic inflammatory diseases of the CNS.