Escartin, C, Galea, Elena, Lakatos, A., O’Callaghan, J.P., Petzold, G.C., Serrano-Pozo, Alberto, Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., Allen, N.J, Araque, Alfonso, Barbeito, Luis, Barzilai, Ari, Bergles, D. E., Bonvento, Gilles, Butt, A.M., Chen, W.T., Cohen-Salmon, M., Cunningham, C., Deneen, B., De Strooper, B., Díaz-Castro, B., Farina, C., Freeman, Mark, Gallo, V., Goldman, J.E., Goldman, S.A., Götz, Magdalena, Gutiérrez, A., Haydon, P. G., Heiland, D.H., Hol, E.M., Holt, M.G., Lino, M., Kastanenka, K.V., Kettenmann, H., Khakh, B.S., Koizumi, S., Lee, C.J., Liddelow, S.A., MacVicar, B.A., Magistretti, P., Messing, A., Mishra, A., Molofsky, A.V., Murai, K.K., Norris, C.M., and Okada, S.
Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters—preferably in vivo—plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions. Funding: CNRS, CEA, ANR, and France Alzheimer to CE.; MCINN (PID2019-107633RB-I00) and Generalitat de Catalunya (2017-SGR547, Grup de demències Sant Pau) to E.G. US Centers for Disease Control and Prevention to J. P.O. Alzheimer’s Association (AACF-17-524184) and NIH-NIA (K08AG064039) to A.S.-P. DFG (SPP1757, STE 552/5, STE 552/4), EU (H2020-MSCA-ITN project 722053 EU-GliaPhD) and BMBF (16GW0182 CONNEXIN) to C.S. Swiss National Science Foundation grant 31003A 173124/1; SNSF NCCR ‘Transcure’ (51NF40-160620); Synapsis Foundation Heidi Seiler-Stiftung 2018-PI01 to A.Volterra. NIH-NINDS (NS084030), Dr. Miriam and Sheldon G. Adelson Medical Foundation and Wings for Life to M.V.S. The authors thank T. Yohannan of Alpha Language Services, Barcelona, for expert copy editing.