The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis

Abstract

Multiple sclerosis (MS) has been classically regarded as a disorder of the white matter of the central nervous system (CNS). However, early alterations of the neuronal compartment occurring in this disorder are partially independent of demyelination. Soluble inflammatory cytokines and glutamate have been proposed as major determinants of neurodegeneration in MS as well as in its experimental animal model, namely experimental autoimmune encephalomyelitis (EAE). The relationship between these two major determinants has been largely elusive. In recent years, unexpected connections have emerged between immune cells and soluble cytokines on the one hand, and synaptic transmission and neurodegeneration on the other. Neurophysiological recordings have recently shown that glutamate-mediated excitatory postsynaptic currents are enhanced during the early phase of EAE, because of altered expression and phosphorylation of AMPA receptors and the downregulation of the immediate early gene Arc/Arg3.1. The synaptic alterations occurring during neuroinflammatory diseases are largely mediated by inflammatory cytokines released from infiltrating T cells and from activated microglia, and are responsible, at least in part, for irreversible dendritic pathology. Collectively, the data covered in this review article suggest that CNS-confined inflammation in MS is associated with the release of soluble molecules, which are capable of altering excitatory synaptic transmission and, finally, of stimulating secondary neurodegenerative gray matter pathology.

Peripheral elevation of TNF-α leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis

“…The increased production of proinflammatory cytokines and infiltration of peripheral immune cells into the central nervous system (CNS) are closely associated with neuronal damage in the spinal cord and many brain regions (6)(7)(8)(9)(10). Elevation of several cytokines such as TNF-α and IFN-γ precedes infiltration of peripheral immune cells and could have a significant impact on neuronal function (11)(12)(13)(14)(15)(16)(17)(18)(19), potentially contributing to early sensory and cognitive impairments.…”

Upregulation of Vascular Endothelial Growth Factor Receptor-3 in the Spinal Cord of Lewis Rats with Experimental Autoimmune Encephalomyelitis

“…Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of multiple sclerosis (MS) in which the immune system attacks myelin protein of the central nervous system (CNS) and leads to inflammatory demyelination and oligodendrocyte loss (Frohman et al 2006;Cassan and Liblau 2007;Compston and Coles 2008;Centonze et al 2010;Moore 2010). Although the precise trigger for MS remains elusive, resident microglia and blood-derived monocytes or macrophages seem to play a central role in the pathogenesis of MS and EAE (for review, see Gandhi et al 2010;Almolda et al 2011;Chastain et al 2011).…”

The Peripheral Network between Oxidative Stress and Inflammation in Multiple Sclerosis

“…It has been universally accepted that neuroinflammation and oxidative stress are simultaneously involved in the pathogenetic processes leading to neurodegeneration in MS (14,15,25). How these two factors are intertwined remains a controversial issue.…”

“…Regarding oxidative stress and inflammatory cells, a detrimental self-sustaining loop may take place: ROS are vigorously released by over-activated inflammatory cells, and can then activate key inflammatory factors, namely Nf-KB (13,14). Indeed, oxidative stress and inflammation are deeply intertwined phenomena during MS pathogenesis, both at peripheral and central levels (7,15,16).…”