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Abstract
Astrocytes play a key role in demyelinating diseases, like multiple sclerosis (MS), although many of their functions remain unknown. The aim of this study was to investigate the impact of astrocyte depletion upon de- and remyelination, inflammation, axonal damage, and virus distribution in Theiler’s murine encephalomyelitis (TME). Groups of two to six glial fibrillary acidic protein (GFAP)-thymidine-kinase transgenic SJL mice and SJL wildtype mice were infected with TME virus (TMEV) or mock (vehicle only). Astrocyte depletion was induced by the intraperitoneal administration of ganciclovir during the early and late phase of TME. The animals were clinically investigated while using a scoring system and a rotarod performance test. Necropsies were performed at 46 and 77 days post infection. Cervical and thoracic spinal cord segments were investigated using hematoxylin and eosin (H&E), luxol fast blue-cresyl violet (LFB), immunohistochemistry targeting Amigo2, aquaporin 4, CD3, CD34, GFAP, ionized calcium-binding adapter molecule 1 (Iba1), myelin basic protein (MBP), non-phosphorylated neurofilaments (np-NF), periaxin, S100A10, TMEV, and immunoelectron microscopy. The astrocyte depleted mice showed a deterioration of clinical signs, a downregulation and disorganization of aquaporin 4 in perivascular astrocytes accompanied by vascular leakage. Furthermore, astrocyte depleted mice showed reduced inflammation and lower numbers of TMEV positive cells in the spinal cord. The present study indicates that astrocyte depletion in virus triggered CNS diseases contributes to a deterioration of clinical signs that are mediated by a dysfunction of perivascular astrocytes.
Highlights
Astrocytes represent the most abundant cell type in the central nervous system (CNS), outnumbering neurons by four- to fivefold [1,2,3,4,5]
Astrocyte depletion in the late phase resulted in a deterioration of clinical signs starting at 72 dpi and rotarod performance at 77 dpi in GSTG when compared with WSTG mice (Figure 1)
Summarized, astrocyte depletion in the early and late phase was associated with a deterioration of clinical signs and rotarod performance
Summary
Astrocytes represent the most abundant cell type in the central nervous system (CNS), outnumbering neurons by four- to fivefold [1,2,3,4,5] They are involved in synapse formation, propagation of action potentials, maintenance of blood-brain (BBB), as well as blood-spinal cord barrier (BSCB), extracellular matrix homeostasis, and antigen presentation [6,7,8,9,10,11]. A1 astrocytes lose several neuroprotective functions and increase the expression of toxic factors (e.g. complement components, neurotoxins), leading to neuronal damage, loss of synapses and an impairment of saltatory conduction downregulating excitatory potentials [6,9,12,15,21]. A2 astrocytes have a rather neuroprotective role, promoting the survival and growth of neurons and supporting synaptic function [3,15,16]
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