Compromised axon initial segment integrity in EAE is preceded by microglial reactivity and contact.
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.
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia.|VCU, Neuroscience Curriculum, Richmond, Virginia.
Kareem C
KC
Clark
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia.
Anna
A
Josephson
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia.|VCU, Neuroscience Curriculum, Richmond, Virginia.
Savannah D
SD
Benusa
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia.
Rebecca K
RK
Hartley
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia.
Matthew
M
Baer
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia.
Suneel
S
Thummala
Department of Research,, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia.
Martha
M
Joslyn
Department of Research,, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia.
Brooke A
BA
Sword
Molecules for Health, Inc, Richmond, Virginia.
Howard
H
Elford
Department of Neurology, VCU, Richmond, Virginia.
Unsong
U
Oh
UPMC/Univ Paris 06 UMR S 1127, Institut Du Cerveau Et De La Moelle Épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, Paris, F-75013, France.
Aysegul
A
Dilsizoglu-Senol
UPMC/Univ Paris 06 UMR S 1127, Institut Du Cerveau Et De La Moelle Épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, Paris, F-75013, France.|AP-HP, Hôpital De La Pitié Salpêtrière, Paris, F-75013, France.
Catherine
C
Lubetzki
UPMC/Univ Paris 06 UMR S 1127, Institut Du Cerveau Et De La Moelle Épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, Paris, F-75013, France.
Marc
M
Davenne
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia.|Department of Research,, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia.
George H
GH
DeVries
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia.|Department of Research,, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia.
Jeffrey L
JL
Dupree
D000818:Animals; D030801:Animals, Genetically Modified; D020274:Autoimmune Diseases of the Nervous System / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D000071040:Axon Initial Segment / Q000502:physiology*; D001369:Axons / Q000473:pathology*; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D003471:Cuprizone / Q000633:toxicity; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006877:Hydroxamic Acids / Q000627:therapeutic use; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D039481:CD11b Antigen; D006877:Hydroxamic Acids; D008996:Monoamine Oxidase Inhibitors; D018800:Thy-1 Antigens; D014409:Tumor Necrosis Factor-alpha; D003471:Cuprizone; D016173:Macrophage Colony-Stimulating Factor; D052247:Nitric Oxide Synthase Type II; C035419:3,4-dihydroxybenzohydroxamic acid
axonal domain; axonal pathology; demyelination; inflammation; multiple sclerosis