TY - JOUR 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 DO - 10.1523/ENEURO.0239-18.2018 SP - ENEURO.0239-18.2018 AU - Aran Groves AU - Yasuyuki Kihara AU - Deepa Jonnalagadda AU - Richard Rivera AU - Grace Kennedy AU - Mark Mayford AU - Jerold Chun Y1 - 2018/09/13 UR - http://www.eneuro.org/content/early/2018/09/13/ENEURO.0239-18.2018.abstract N2 - 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 “ieAstrocytes (immediate-early astrocytes)” 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 (3-D 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. Over 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.Significant Statement A new, functionally defined in vivo subpopulation of astrocytes termed “ieAstrocytes (immediate-early astrocytes)” was identified as the first and predominant CNS cell type showing c-Fos activation, in an animal model of multiple sclerosis (MS). ieAstrocytes track with disease severity. The approved MS drug, fingolimod (FTY720, an S1P receptor modulator) reduced ieAstrocyte formation as well as clinical disease. Agents that prevent or reduce ieAstrocytes could represent a new strategic target for treating MS and other neuroinflammatory and neurodegenerative brain disorders. ER -