1. Compromised axon initial segment integrity in EAE is preceded by microglial reactivity and contact.
- Author
-
Clark KC, Josephson A, Benusa SD, Hartley RK, Baer M, Thummala S, Joslyn M, Sword BA, Elford H, Oh U, Dilsizoglu-Senol A, Lubetzki C, Davenne M, DeVries GH, and Dupree JL
- 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, CD11b Antigen genetics, CD11b Antigen metabolism, Cell Death physiology, Cells, Cultured, Cuprizone toxicity, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental chemically induced, Encephalomyelitis, Autoimmune, Experimental drug therapy, Encephalomyelitis, Autoimmune, Experimental immunology, Gene Expression Regulation drug effects, Hydroxamic Acids therapeutic use, Macrophage Colony-Stimulating Factor genetics, Macrophage Colony-Stimulating Factor metabolism, Mice, Mice, Inbred C57BL, Microglia drug effects, Monoamine Oxidase Inhibitors toxicity, Nitric Oxide Synthase Type II genetics, Nitric Oxide Synthase Type II metabolism, Thy-1 Antigens genetics, Thy-1 Antigens metabolism, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Axon Initial Segment physiology, Axons pathology, Encephalomyelitis, Autoimmune, Experimental pathology, Gene Expression Regulation physiology, Microglia metabolism
- Abstract
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., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
- View/download PDF