Connexin pathology in chronic multiple sclerosis and experimental autoimmune encephalomyelitis

Abstract

AbstractCentral nervous system (CNS) glia are extensively coupled through gap junctions (GJ) formed by a highly cell‐specific set of connexins. Recently characterized inherited human disorders and respective animal models highlight the crucial role of glial GJ in CNS myelination and homeostasis. These emerging roles of connexins have generated interest into their possible involvement in common acquired demyelinating disorders, especially multiple sclerosis (MS). Analysis of post‐mortem brain samples from MS patients, including morphological, biochemical, and gene expression studies, showed significant alteration in glial connexins not only in lesions, but also extending into the normal appearing white matter (NAWM). Compared with non‐MS cases, the oligodendrocyte connexins, Cx32 and Cx47, were reduced in and around chronic MS lesions, whereas Cx43, the major astrocytic partner in oligodendrocyte–astrocyte (O/A) GJ, was increased, reflecting astrogliosis. Furthermore, in the NAWM, Cx32 GJ were significantly reduced along myelinated fibers, whereas Cx47 showed increased expression mainly in oligodendrocyte precursor cells (OPC). However, OPC showed only limited connectivity to astrocytes. These alterations were replicated in the experimental autoimmune encephalomyelitis (EAE) model, with persistent loss of Cx47 and Cx32 GJ even away from lesions. Additionally, Cx43 was severely reduced in acute EAE with disruption of O/A GJ, followed by increased Cx43 expression at chronic stages of astrogliosis, but without complete re‐establishment of GJ to oligodendrocytes. Thus, loss of oligodendrocyte GJ in myelinated fibers, and disrupted O/A GJ connectivity in MS lesions and in NAWM in the setting of persistent inflammation and astrogliosis emerge as important aspects of MS pathology, and might have implications for disease progression.