RT Journal Article
SR Electronic
T1 A Functionally Defined <em>In Vivo</em> Astrocyte Population Identified by c-Fos Activation in a Mouse Model of Multiple Sclerosis Modulated by S1P Signaling: Immediate-Early Astrocytes (<em>ieAstrocytes</em>)
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0239-18.2018
DO 10.1523/ENEURO.0239-18.2018
VO 5
IS 5
A1 Aran Groves
A1 Yasuyuki Kihara
A1 Deepa Jonnalagadda
A1 Richard Rivera
A1 Grace Kennedy
A1 Mark Mayford
A1 Jerold Chun
YR 2018
UL http://www.eneuro.org/content/5/5/ENEURO.0239-18.2018.abstract
AB Astrocytes have prominent roles in central nervous system (CNS) function and disease, with subpopulations defined primarily by morphologies and molecular markers often determined in cell culture. Here, we identify an in vivo astrocyte subpopulation termed immediate-early astrocytes (ieAstrocytes) that is defined by functional c-Fos activation during CNS disease development. An unbiased screen for CNS cells showing c-Fos activation during experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS), was developed by using inducible, TetTag c-Fos reporter mice that label activated cells with a temporally stable, nuclear green fluorescent protein (GFP). Four-dimensional (3D over time) c-Fos activation maps in the spinal cord were produced by combining tissue clearing (iDISCO) and confocal microscopy that identified onset and expansion of GFP+ cell populations during EAE. More than 95% of the GFP+ cells showed glial fibrillary acidic protein (GFAP) immunoreactivity—in contrast to absent or rare labeling of neurons, microglia, and infiltrating immune cells—which constituted ieAstrocytes that linearly increased in number with progression of EAE. ieAstrocyte formation was reduced by either astrocyte-specific genetic removal of sphingosine 1-phosphate receptor 1 (S1P1) or pharmacological inhibition by fingolimod (FTY720), an FDA-approved MS medicine that can functionally antagonize S1P1. ieAstrocytes thus represent a functionally defined subset of disease-linked astrocytes that are the first and predominant CNS cell population activated during EAE, and that track with disease severity in vivo. Their reduction by a disease-modifying agent supports their therapeutic relevance to MS and potentially other neuroinflammatory and neurodegenerative diseases.