Compromised axon initial segment integrity in EAE is preceded by microglial reactivity and contact

• Published in: Glia Vol. 64; no. 7; pp. 1190 - 1209
• Main Authors: Clark, Kareem C., Josephson, Anna, Benusa, Savannah D., Hartley, Rebecca K., Baer, Matthew, Thummala, Suneel, Joslyn, Martha, Sword, Brooke A., Elford, Howard, Oh, Unsong, Dilsizoglu-Senol, Aysegul, Lubetzki, Catherine, Davenne, Marc, DeVries, George H., Dupree, Jeffrey L.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-07-2016; Wiley Subscription Services, Inc
• Subjects: Animals; Animals, Genetically Modified; Autoimmune Diseases of the Nervous System - chemically induced; Autoimmune Diseases of the Nervous System - drug therapy; Autoimmune Diseases of the Nervous System - pathology; Axon Initial Segment - physiology; axonal domain; axonal pathology; Axons - pathology; CD11b Antigen - genetics; CD11b Antigen - metabolism; Cell Death - physiology; Cells, Cultured; Cuprizone - toxicity; demyelination; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - chemically induced; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Hydroxamic Acids - therapeutic use; inflammation; Macrophage Colony-Stimulating Factor - genetics; Macrophage Colony-Stimulating Factor - metabolism; Mice; Mice, Inbred C57BL; Microglia - drug effects; Microglia - metabolism; Monoamine Oxidase Inhibitors - toxicity; multiple sclerosis; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Pathology; Rodents; Thy-1 Antigens - genetics; Thy-1 Antigens - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; axonal domain; axonal pathology; inflammation; demyelination; multiple sclerosis
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22991

Axonal pathology is a key contributor to long‐term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal pathology in MS remain elusive. Evidence suggests that axonal pathology is a direct consequence of demyelination, as we and others have shown that the node of Ranvier disassembles following loss of myelin. In contrast to the node of Ranvier, we now show that the axon initial segment (AIS), the axonal domain responsible for action potential initiation, remains intact following cuprizone‐induced cortical demyelination. Instead, we find that the AIS is disrupted in the neocortex of mice that develop experimental autoimmune encephalomyelitis (EAE) independent of local demyelination. EAE‐induced mice demonstrate profound compromise of AIS integrity with a progressive disruption that corresponds to EAE clinical disease severity and duration, in addition to cortical microglial reactivity. Furthermore, treatment with the drug didox results in attenuation of AIS pathology concomitantly with microglial reversion to a less reactive state. Together, our findings suggest that inflammation, but not demyelination, disrupts AIS integrity and that therapeutic intervention may protect and reverse this pathology. GLIA 2016;64:1190–1209
Main Points
AIS disruption is independent of demyelination but correlates with EAE‐induced microglial reactivity and contact.
Treatment with an anti‐inflammatory attenuates AIS integrity, providing the first evidence that AIS pathology is reversible.