Khakh, B. S. & Deneen, B. The emerging nature of astrocyte diversity. Annu. Rev. Neurosci. 42, 187–207 (2019). This review emphasizes that astrocytes are diverse and have properties and functions specific to particular brain areas and diseases; gaps in our understanding of astrocyte diversity and its physiological relevance in the CNS are identified.

Article  PubMed  CAS  Google Scholar 

Archie, S. R., Al Shoyaib, A. & Cucullo, L. Blood-brain barrier dysfunction in CNS disorders and putative therapeutic targets: an overview. Pharmaceutics 13, 1779 (2021).

Article  PubMed  PubMed Central  CAS  Google Scholar 

MacVicar, B. A. & Newman, E. A. Astrocyte regulation of blood flow in the brain. Cold Spring Harb. Perspect. Biol. 7, a020388 (2015).

Article  PubMed  PubMed Central  Google Scholar 

Araque, A., Parpura, V., Sanzgiri, R. P. & Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215 (1999).

Article  PubMed  CAS  Google Scholar 

Devinsky, O., Vezzani, A., Najjar, S., De Lanerolle, N. C. & Rogawski, M. A. Glia and epilepsy: excitability and inflammation. Trends Neurosci. 36, 174–184 (2013).

Article  PubMed  CAS  Google Scholar 

Verhoog, Q. P., Holtman, L., Aronica, E. & van Vliet, E. A. Astrocytes as guardians of neuronal excitability: mechanisms underlying epileptogenesis. Front. Neurol. 11, 591690 (2020).

Article  PubMed  PubMed Central  Google Scholar 

Escartin, C. et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci. 24, 312–325 (2021).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Middeldorp, J. & Hol, E. M. GFAP in health and disease. Prog. Neurobiol. 93, 421–443 (2011).

Article  PubMed  CAS  Google Scholar 

Ammothumkandy, A. et al. Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy. Nat. Neurosci. 25, 493–503 (2022). This study shows that a longer duration of epilepsy is associated with a sharp decline in neurogenesis but maintained astrogenesis, and that immature neurons in mesial TLE are mostly inactive but the activity of immature astrocytes in the hippocampus depends on epileptiform-like activity.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Yang, L. et al. Astrocyte activation and memory impairment in the repetitive febrile seizures model. Epilepsy Res. 86, 209–220 (2009).

Article  PubMed  CAS  Google Scholar 

Devinsky, O. et al. Epilepsy. Nat. Rev. Dis. Prim. 4, 18024 (2018).

Article  PubMed  Google Scholar 

Bedner, P., Jabs, R. & Steinhäuser, C. Properties of human astrocytes and NG2 glia. Glia 68, 756–767 (2020).

Article  PubMed  Google Scholar 

Li, J. et al. Conservation and divergence of vulnerability and responses to stressors between human and mouse astrocytes. Nat. Commun. 12, 3958 (2021).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Eid, T., Tu, N., Lee, T.-S. W. & Lai, J. C. K. Regulation of astrocyte glutamine synthetase in epilepsy. Neurochem. Int. 63, 670–681 (2013).

Article  PubMed  CAS  Google Scholar 

Bedner, P. et al. Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain 138, 1208–1222 (2015). This study provides the first direct evidence that loss of astrocytic gap junction coupling has a key role in the initiation and progression of epilepsy.

Article  PubMed  PubMed Central  Google Scholar 

Messing, A., Brenner, M., Feany, M. B., Nedergaard, M. & Goldman, J. E. Alexander disease. J. Neurosci. 32, 5017–5023 (2012).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Feige, L., Zaeck, L. M., Sehl-Ewert, J., Finke, S. & Bourhy, H. Innate immune signaling and role of glial cells in herpes simplex virus- and rabies virus-induced encephalitis. Viruses 13, 2364 (2021).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Robel, S. et al. Reactive astrogliosis causes the development of spontaneous seizures. J. Neurosci. 35, 3330–3345 (2015).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Ortinski, P. I. et al. Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat. Neurosci. 13, 584–591 (2010).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Shao, L. et al. Silencing of circIgf1r plays a protective role in neuronal injury via regulating astrocyte polarization during epilepsy. FASEB J. 35, e21330 (2021).

Article  PubMed  CAS  Google Scholar 

Sano, F. et al. Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus. JCI Insight 6, 135391 (2021).

Article  PubMed  Google Scholar 

Maupu, C. et al. Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice. Neurobiol. Dis. 152, 105276 (2021).

Article  PubMed  CAS  Google Scholar 

Aronica, E., Ravizza, T., Zurolo, E. & Vezzani, A. Astrocyte immune response in epilepsy. Glia 60, 1258–1268 (2012).

Article  PubMed  Google Scholar 

Vezzani, A., Balosso, S. & Ravizza, T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat. Rev. Neurol. 15, 459–472 (2019).

Article  PubMed  CAS  Google Scholar 

Klein, P. et al. Commonalities in epileptogenic processes from different acute brain insults: do they translate? Epilepsia 59, 37–66 (2018).

Article  PubMed  CAS  Google Scholar 

Bushong, E. A., Martone, M. E., Jones, Y. Z. & Ellisman, M. H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J. Neurosci. 22, 183–192 (2002).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Savtchouk, I. & Volterra, A. Gliotransmission: beyond black-and-white. J. Neurosci. 38, 14–25 (2018).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Fiacco, T. A. & McCarthy, K. D. Multiple lines of evidence indicate that gliotransmission does not occur under physiological conditions. J. Neurosci. 38, 3–13 (2018).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Parpura, V. et al. Glutamate-mediated astrocyte–neuron signalling. Nature 369, 744–747 (1994).

Article  PubMed  CAS  Google Scholar 

Nedergaard, M. Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science 263, 1768–1771 (1994).

Article  PubMed  CAS  Google Scholar 

Bezzi, P. et al. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat. Neurosci. 7, 613 (2004). This study provides the first proof that transmitter vesicles are present in astrocytes in situ.

Article  PubMed  CAS  Google Scholar 

Bohmbach, K., Schwarz, M. K., Schoch, S. & Henneberger, C. The structural and functional evidence for vesicular release from astrocytes in situ. Brain Res. Bull. 136, 65–75 (2018).

Article  PubMed  CAS  Google Scholar 

Fellin, T. et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43, 729–743 (2004).

Article  PubMed  CAS  Google Scholar 

Angulo, M. C., Kozlov, A. S., Charpak, S. & Audinat, E. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J. Neurosci. 24, 6920–6927 (2004).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Jourdain, P. et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. 10, 331–339 (2007).

Article  PubMed  CAS  Google Scholar 

Araque, A., Castillo, P. E., Manzoni, O. J. & Tonini, R. Synaptic functions of endocannabinoid signaling in health and disease. Neuropharmacology 124, 13–24 (2017).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Henneberger, C., Papouin, T., Oliet, S. H. R. & Rusakov, D. A. Long-term potentiation depends on release of D-serine from astrocytes. Nature 463, 232–236 (2010).

Article