Abstract
Astrocytes are abundant glial cells in the central nervous system (CNS) that perform diverse functions in health and disease. Astrocyte dysfunction is found in numerous diseases, including multiple sclerosis, Alzheimer disease, Parkinson disease, Huntington disease and neuropsychiatric disorders. Astrocytes regulate glutamate and ion homeostasis, cholesterol and sphingolipid metabolism and respond to environmental factors, all of which have been implicated in neurological diseases. Astrocytes also exhibit significant heterogeneity, driven by developmental programmes and stimulus-specific cellular responses controlled by CNS location, cell–cell interactions and other mechanisms. In this Review, we highlight general mechanisms of astrocyte regulation and their potential as therapeutic targets, including drugs that alter astrocyte metabolism, and therapies that target transporters and receptors on astrocytes. Emerging ideas, such as engineered probiotics and glia-to-neuron conversion therapies, are also discussed. We further propose a concise nomenclature for astrocyte subsets that we use to highlight the roles of astrocytes and specific subsets in neurological diseases.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Allen, N. J. & Lyons, D. A. Glia as architects of central nervous system formation and function. Science 362, 181–185 (2018).
Freeman, M. R. Specification and morphogenesis of astrocytes. Science 330, 774–778 (2010).
Virchow, R. Gesammelte Abhandlungen zur Wissenschaftlichen Medizin (Meidinger Sohn & Co., 1856).
Golgi, C. Contribuzione alla fina Anatomia Degli Organi Centrali del Sistema Nervosos (Tipi Fava e Garagnani, 1871).
Kölliker, A. Handbuch der Gewebelehre des Menschen (Wilhelm Engelmann, 1889).
Andriezen, W. L. The neuroglia elements in the human brain. BMJ 2, 227–230 (1893).
Garcia-Marin, V., Garcia-Lopez, P. & Freire, M. Cajal’s contributions to glia research. Trends Neurosci. 30, 479–487 (2007).
Sanmarco, L. M. et al. Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes. Nature 590, 473–479 (2021).
Wheeler, M. A. et al. MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593–599 (2020). This paper was the first to identify heterogeneity among astrocytes in neurological disease in an unsupervised manner using scRNA-seq and by validating a disease-associated astrocyte subset.
Habib, N. et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23, 701–706 (2020). Detailed analysis of disease-associated astrocytes in AD.
Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014.e1022 (2018).
Zeisel, A. et al. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347, 1138–1142 (2015).
Saunders, A. et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174, 1015–1030.e1016 (2018).
Bayraktar, O. A. et al. Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map. Nat. Neurosci. 23, 500–509 (2020).
Clark, I. C. et al. Barcoded viral tracing of single-cell interactions in central nervous system inflammation. Science 372, eabf1230 (2021). This paper describes the development of RABID-seq as a method for the study of astrocyte interactions in vivo using molecular barcoding and scRNA-seq. Astrocyte interactions can be mapped at single-cell resolution.
Liddelow, S. A. & Barres, B. A. Reactive astrocytes: production, function, and therapeutic potential. Immunity 46, 957–967 (2017).
Lanjakornsiripan, D. et al. Layer-specific morphological and molecular differences in neocortical astrocytes and their dependence on neuronal layers. Nat. Commun. 9, 1623 (2018).
Mayo, L. et al. IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation. Brain 139, 1939–1957 (2016).
Mayo, L. et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat. Med. 20, 1147–1156 (2014).
Rothhammer, V. et al. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724–728 (2018). This work demonstrates for the first time that astrocyte–microglia interactions during CNS inflammation are regulated by the gut commensal flora.
Rothhammer, V. et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 22, 586–597 (2016). First report of the control of astrocyte transcriptional programmes in CNS inflammation by the GBA via specific microbial metabolites.
Linnerbauer, M., Wheeler, M. A. & Quintana, F. J. Astrocyte crosstalk in CNS inflammation. Neuron 108, 608–622 (2020).
Giovannoni, F. & Quintana, F. J. The role of astrocytes in CNS inflammation. Trends Immunol. 41, 805–819 (2020).
Wheeler, M. A. & Quintana, F. J. Regulation of astrocyte functions in multiple sclerosis. Cold Spring Harb. Perspect. Med. 9, a029009 (2019).
Rothhammer, V. & Quintana, F. J. Control of autoimmune CNS inflammation by astrocytes. Semin. Immunopathol. 37, 625–638 (2015).
Wheeler, M. A. et al. Environmental control of astrocyte pathogenic activities in CNS inflammation. Cell 176, 581–596.e518 (2019).
Itoh, N. et al. Cell-specific and region-specific transcriptomics in the multiple sclerosis model: focus on astrocytes. Proc. Natl Acad. Sci. USA 115, E302–E309 (2018).
Spence, R. D. et al. Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERalpha signaling on astrocytes but not through ERbeta signaling on astrocytes or neurons. J. Neurosci. 33, 10924–10933 (2013).
Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019).
Zhou, Y. et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat. Med. 26, 131–142 (2020).
Yun, S. P. et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. 24, 931–938 (2018).
Booth, H. D. E., Hirst, W. D. & Wade-Martins, R. The role of astrocyte dysfunction in Parkinson’s disease pathogenesis. Trends Neurosci. 40, 358–370 (2017).
Khakh, B. S. et al. Unravelling and exploiting astrocyte dysfunction in Huntington’s disease. Trends Neurosci. 40, 422–437 (2017).
Tong, X. et al. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat. Neurosci. 17, 694–703 (2014). A molecularly defined validation of a disease-associated astrocyte subset in a HD model.
Wu, Z. et al. Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease. Nat. Commun. 11, 1105 (2020).
Diaz-Castro, B., Gangwani, M. R., Yu, X., Coppola, G. & Khakh, B. S. Astrocyte molecular signatures in Huntington’s disease. Sci. Transl. Med. 11, eaaw8546 (2019).
Yu, X. et al. Context-specific striatal astrocyte molecular responses are phenotypically exploitable. Neuron 108, 1146–1162 e1110 (2020).
Yu, X. et al. Reducing astrocyte calcium signaling in vivo alters striatal microcircuits and causes repetitive behavior. Neuron 99, 1170–1187 e1179 (2018). Comprehensive report demonstrating the role of astrocyte calcium signalling in controlling behaviour and neural activity in the striatum.
Martin-Fernandez, M. et al. Synapse-specific astrocyte gating of amygdala-related behavior. Nat. Neurosci. 20, 1540–1548 (2017).
Adamsky, A. et al. Astrocytic activation generates de novo neuronal potentiation and memory enhancement. Cell 174, 59–71.e14 (2018). First report of bona fide astrocyte control over memory by potentiating synaptic transmission in the hippocampus.
Nagai, J. et al. Hyperactivity with disrupted attention by activation of an astrocyte synaptogenic cue. Cell 177, 1280–1292.e1220 (2019).
Nagai, J. et al. Behaviorally consequential astrocytic regulation of neural circuits. Neuron 109, 576–596 (2021).
Molofsky, A. V. & Deneen, B. Astrocyte development: a guide for the perplexed. Glia 63, 1320–1329 (2015).
Ge, W. P., Miyawaki, A., Gage, F. H., Jan, Y. N. & Jan, L. Y. Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484, 376–380 (2012).
Volterra, A. & Meldolesi, J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat. Rev. Neurosci. 6, 626–640 (2005).
Alvarez, J. I., Katayama, T. & Prat, A. Glial influence on the blood brain barrier. Glia 61, 1939–1958 (2013).
Abbott, N. J., Ronnback, L. & Hansson, E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7, 41–53 (2006).
Mastorakos, P. & McGavern, D. The anatomy and immunology of vasculature in the central nervous system. Sci. Immunol. 4, eaav0492 (2019).
Obermeier, B., Daneman, R. & Ransohoff, R. M. Development, maintenance and disruption of the blood-brain barrier. Nat. Med. 19, 1584–1596 (2013).
Sofroniew, M. V. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249–263 (2015).
Foo, L. C. et al. Development of a method for the purification and culture of rodent astrocytes. Neuron 71, 799–811 (2011).
Owens, T., Bechmann, I. & Engelhardt, B. Perivascular spaces and the two steps to neuroinflammation. J. Neuropathol. Exp. Neurol. 67, 1113–1121 (2008).
Engelhardt, B. & Coisne, C. Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids Barriers CNS 8, 4 (2011).
Alvarez, J. I. et al. The hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334, 1727–1731 (2011).
Bell, R. D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012).
Argaw, A. T. et al. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J. Clin. Invest. 122, 2454–2468 (2012).
Argaw, A. T., Gurfein, B. T., Zhang, Y., Zameer, A. & John, G. R. VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc. Natl Acad. Sci. USA 106, 1977–1982 (2009).
Araque, A., Parpura, V., Sanzgiri, R. P. & Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215 (1999).
Chung, W. S., Allen, N. J. & Eroglu, C. Astrocytes control synapse formation, function, and elimination. Cold Spring Harb. Perspect. Biol. 7, a020370 (2015).
Martin, R., Bajo-Graneras, R., Moratalla, R., Perea, G. & Araque, A. Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways. Science 349, 730–734 (2015). This study validates functional astrocyte heterogeneity in the context of striatal microcircuit regulation and implicates defined pathways that controlled astrocyte–neuron communication.
Khakh, B. S. & Sofroniew, M. V. Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18, 942–952 (2015).
Shigetomi, E., Patel, S. & Khakh, B. S. Probing the complexities of astrocyte calcium signaling. Trends Cell Biol. 26, 300–312 (2016).
Araque, A. et al. Gliotransmitters travel in time and space. Neuron 81, 728–739 (2014).
Volterra, A., Liaudet, N. & Savtchouk, I. Astrocyte Ca2+ signalling: an unexpected complexity. Nat. Rev. Neurosci. 15, 327–335 (2014).
Halassa, M. M. & Haydon, P. G. Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu. Rev. Physiol. 72, 335–355 (2010).
Somjen, G. G. Ion regulation in the brain: implications for pathophysiology. Neuroscientist 8, 254–267 (2002).
Silver, I. A., Deas, J. & Erecinska, M. Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells. Neuroscience 78, 589–601 (1997).
Hu, Z. L. et al. Kir6.1/K-ATP channel on astrocytes protects against dopaminergic neurodegeneration in the MPTP mouse model of Parkinson’s disease via promoting mitophagy. Brain Behav. Immun. 81, 509–522 (2019).
Chen, M. M., Hu, Z. L., Ding, J. H., Du, R. H. & Hu, G. Astrocytic Kir6.1 deletion aggravates neurodegeneration in the lipopolysaccharide-induced mouse model of Parkinson’s disease via astrocyte-neuron cross talk through complement C3-C3R signaling. Brain Behav. Immun. 95, 310–320 (2021).
Duan, S., Anderson, C. M., Stein, B. A. & Swanson, R. A. Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. J. Neurosci. 19, 10193–10200 (1999).
Anderson, C. M. & Swanson, R. A. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32, 1–14 (2000).
Schousboe, A. & Waagepetersen, H. S. Role of astrocytes in glutamate homeostasis: implications for excitotoxicity. Neurotox. Res. 8, 221–225 (2005).
Dong, X.-X., Wang, Y. & Qin, Z.-H. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol. Sin. 30, 379–387 (2009).
Maragakis, N. J. & Rothstein, J. D. Glutamate transporters: animal models to neurologic disease. Neurobiol. Dis. 15, 461–473 (2004).
Soni, N., Reddy, B. V. & Kumar, P. GLT-1 transporter: an effective pharmacological target for various neurological disorders. Pharmacol. Biochem. Behav. 127, 70–81 (2014).
Doble, A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol. Ther. 81, 163–221 (1999).
Pitt, D., Werner, P. & Raine, C. S. Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. 6, 67–70 (2000).
Santello, M. & Volterra, A. TNFalpha in synaptic function: switching gears. Trends Neurosci. 35, 638–647 (2012).
Fiacco, T. A. & McCarthy, K. D. Astrocyte calcium elevations: properties, propagation, and effects on brain signaling. Glia 54, 676–690 (2006).
Zorec, R. et al. Astroglial excitability and gliotransmission: an appraisal of Ca2+ as a signalling route. ASN Neuro 4, e00080 (2012).
Lee, S. et al. Channel-mediated tonic GABA release from glia. Science 330, 790–796 (2010).
Parpura, V. et al. Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747 (1994).
Queiroz, G., Gebicke-Haerter, P. J., Schobert, A., Starke, K. & von Kugelgen, I. Release of ATP from cultured rat astrocytes elicited by glutamate receptor activation. Neuroscience 78, 1203–1208 (1997).
Stout, C. E., Costantin, J. L., Naus, C. C. & Charles, A. C. Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J. Biol. Chem. 277, 10482–10488 (2002).
Jo, S. et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat. Med. 20, 886–896 (2014).
Wu, Z., Guo, Z., Gearing, M. & Chen, G. Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s [corrected] disease model. Nat. Commun. 5, 4159 (2014).
Bélanger, M., Allaman, I. & Magistretti, J. P. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 14, 724–738 (2011).
Magistretti, P. J. & Allaman, I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19, 235–249 (2018).
Sonninen, T. M. et al. Metabolic alterations in Parkinson’s disease astrocytes. Sci. Rep. 10, 14474 (2020).
Merlini, M., Meyer, E. P., Ulmann-Schuler, A. & Nitsch, R. M. Vascular beta-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAbeta mice. Acta Neuropathol. 122, 293–311 (2011).
Polyzos, A. A. et al. Metabolic reprogramming in astrocytes distinguishes region-specific neuronal susceptibility in huntington mice. Cell Metab. 29, 1258–1273 e1211 (2019).
Acuña, A. I. et al. A failure in energy metabolism and antioxidant uptake precede symptoms of Huntington’s disease in mice. Nature Commun. 4, 2917 (2013).
Chao, C. C. et al. Metabolic control of astrocyte pathogenic activity via cPLA2-MAVS. Cell 179, 1483–1498.e1422 (2019).
Ferraiuolo, L. et al. Dysregulation of astrocyte-motoneuron cross-talk in mutant superoxide dismutase 1-related amyotrophic lateral sclerosis. Brain 134, 2627–2641 (2011).
Escartin, C. et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci. 24, 312–325 (2021). A recent consensus statement defining the hallmarks and open questions that surround astrocyte heterogeneity and reactivity.
Anderson, M. A., Ao, Y. & Sofroniew, M. V. Heterogeneity of reactive astrocytes. Neurosci. Lett. 565, 23–29 (2014).
Safieh-Garabedian, B., Mayasi, Y. & Saade, N. E. Targeting neuroinflammation for therapeutic intervention in neurodegenerative pathologies: a role for the peptide analogue of thymulin (PAT). Expert Opin. Ther. Targets 16, 1065–1073 (2012).
Farina, C., Aloisi, F. & Meinl, E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 28, 138–145 (2007).
Colombo, E. & Farina, C. Astrocytes: key regulators of neuroinflammation. Trends Immunol. 37, 608–620 (2016).
Silver, J. & Miller, J. H. Regeneration beyond the glial scar. Nat. Rev. Neurosci. 5, 146–156 (2004).
Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016). Seminal study describing molecular mechanisms by which astrocytes control regeneration following SCI.
Anderson, M. A. et al. Required growth facilitators propel axon regeneration across complete spinal cord injury. Nature 561, 396–400 (2018).
Tak, P. P. & Firestein, G. S. NF-kappaB: a key role in inflammatory diseases. J. Clin. Invest. 107, 7–11 (2001).
Mattson, M. P. & Camandola, S. NF-κB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest. 107, 247–254 (2001).
Kang, Z. et al. Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 32, 414–425 (2010).
Liu, J. & Du, L. PERK pathway is involved in oxygen-glucose-serum deprivation-induced NF-kB activation via ROS generation in spinal cord astrocytes. Biochem. Biophys. Res. Commun. 467, 197–203 (2015).
Kawai, T. & Akira, S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol. Med. 13, 460–469 (2007).
Brambilla, R. et al. Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J. Exp. Med. 202, 145–156 (2005).
Brambilla, R. et al. Transgenic inhibition of astroglial NF-κB protects from optic nerve damage and retinal ganglion cell loss in experimental optic neuritis. J. Neuroinflammation 9, 213 (2012).
Brambilla, R. et al. Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J. Immunol. 182, 2628–2640 (2009).
Brambilla, R. et al. Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. Glia 62, 452–467 (2014).
van Loo, G. et al. Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat. Immunol. 7, 954–961 (2006).
Carrero, I. et al. Oligomers of β-amyloid protein (Aβ1-42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1β, tumour necrosis factor-α, and a nuclear factor κB mechanism in the rat brain. Exp. Neurol. 236, 215–227 (2012).
Lian, H. et al. NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron 85, 101–115 (2015).
Hsiao, H. Y., Chen, Y. C., Chen, H. M., Tu, P. H. & Chern, Y. A critical role of astrocyte-mediated nuclear factor-κB-dependent inflammation in Huntington’s disease. Hum. Mol. Genet. 22, 1826–1842 (2013).
Ben Haim, L. et al. The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer’s and Huntington’s diseases. J. Neurosci. 35, 2817–2829 (2015).
Ceyzeriat, K., Abjean, L., Carrillo-de Sauvage, M. A., Ben Haim, L. & Escartin, C. The complex STATes of astrocyte reactivity: how are they controlled by the JAK-STAT3 pathway? Neuroscience 330, 205–218 (2016).
Zhong, Z., Wen, Z. & Darnell, J. E. Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Proc. Natl Acad. Sci. USA 91, 4806–4810 (1994).
He, F. et al. A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat. Neurosci. 8, 616–625 (2005).
Shibata, N. et al. Activation of signal transducer and activator of transcription-3 in the spinal cord of sporadic amyotrophic lateral sclerosis patients. Neurodegener. Dis. 6, 118–126 (2009).
Shibata, N. et al. Activation of STAT3 and inhibitory effects of pioglitazone on STAT3 activity in a mouse model of SOD1-mutated amyotrophic lateral sclerosis. Neuropathology 30, 353–360 (2010).
Reichenbach, N. et al. Inhibition of Stat3-mediated astrogliosis ameliorates pathology in an Alzheimer’s disease model. EMBO Mol. Med. 11, e9665 (2019).
Haroon, F. et al. Gp130-dependent astrocytic survival is critical for the control of autoimmune central nervous system inflammation. J. Immunol. 186, 6521–6531 (2011).
Lu, H. C. et al. STAT3 signaling in myeloid cells promotes pathogenic myelin-specific T cell differentiation and autoimmune demyelination. Proc. Natl Acad. Sci. USA 117, 5430–5441 (2020).
Lu, J. Q., Power, C., Blevins, G., Giuliani, F. & Yong, V. W. The regulation of reactive changes around multiple sclerosis lesions by phosphorylated signal transducer and activator of transcription. J. Neuropathol. Exp. Neurol. 72, 1135–1144 (2013).
Klee, C. B., Crouch, T. H. & Krinks, M. H. Calcineurin: a calcium- and calmodulin-binding protein of the nervous system. Proc. Natl Acad. Sci. USA 76, 6270–6273 (1979).
Hogan, P. G. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 17, 2205–2232 (2003).
Furman, J. L. & Norris, C. M. Calcineurin and glial signaling: neuroinflammation and beyond. J. Neuroinflammation 11, 158 (2014).
Serrano-Perez, M. C. et al. Response of transcription factor NFATc3 to excitotoxic and traumatic brain insults: identification of a subpopulation of reactive astrocytes. Glia 59, 94–107 (2011).
Furman, J. L. et al. Blockade of astrocytic calcineurin/NFAT signaling helps to normalize hippocampal synaptic function and plasticity in a rat model of traumatic brain injury. J. Neurosci. 36, 1502–1515 (2016).
Abdul, H. M., Furman, J. L., Sama, M. A., Mathis, D. M. & Norris, C. M. NFATs and Alzheimer’s disease. Mol. Cell Pharmacol. 2, 7–14 (2010).
Caraveo, G. et al. Calcineurin determines toxic versus beneficial responses to α-synuclein. Proc. Natl Acad. Sci. USA 111, E3544–E3552 (2014).
Furman, J. L. et al. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J. Neurosci. 32, 16129–16140 (2012).
Sompol, P. et al. Calcineurin/NFAT signaling in activated astrocytes drives network hyperexcitability in Aβ-bearing mice. J. Neurosci. 37, 6132–6148 (2017).
Choe, J. Y., Park, K. Y., Park, S. H., Lee, S. I. & Kim, S. K. Regulatory effect of calcineurin inhibitor, tacrolimus, on IL-6/sIL-6R-mediated RANKL expression through JAK2-STAT3-SOCS3 signaling pathway in fibroblast-like synoviocytes. Arthritis Res. Ther. 15, R26 (2013).
Hirano, K. et al. Differential effects of calcineurin inhibitors, tacrolimus and cyclosporin a, on interferon-induced antiviral protein in human hepatocyte cells. Liver Transpl. 14, 292–298 (2008).
Manukyan, I., Galatioto, J., Mascareno, E., Bhaduri, S. & Siddiqui, M. A. Cross-talk between calcineurin/NFAT and Jak/STAT signalling induces cardioprotective alphaB-crystallin gene expression in response to hypertrophic stimuli. J. Cell Mol. Med. 14, 1707–1716 (2010).
Mencarelli, A. et al. Calcineurin B in CD4+ T cells prevents autoimmune colitis by negatively regulating the JAK/STAT pathway. Front. Immunol. 9, 261 (2018).
Filippi, M. et al. Multiple sclerosis. Nat. Rev. Dis. Prim. 4, 43 (2018).
Faissner, S., Plemel, J. R., Gold, R. & Yong, V. W. Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat. Rev. Drug Discov. 18, 905–922 (2019).
JM, C. Histologie de la sclérose en plaque [Histology of multiple sclerosis]. Gaz. des. Hôpitaux 41, 554–555 (1868).
Liedtke, W., Edelmann, W., Chiu, F. C., Kucherlapati, R. & Raine, C. S. Experimental autoimmune encephalomyelitis in mice lacking glial fibrillary acidic protein is characterized by a more severe clinical course and an infiltrative central nervous system lesion. Am. J. Pathol. 152, 251–259 (1998).
Voskuhl, R. R. et al. Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS. J. Neurosci. 29, 11511–11522 (2009).
Toft-Hansen, H., Fuchtbauer, L. & Owens, T. Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease. Glia 59, 166–176 (2011).
Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
Farez, M. F. et al. Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE. Nat. Immunol. 10, 958–964 (2009).
Moreno, M. et al. Conditional ablation of astroglial CCL2 suppresses CNS accumulation of M1 macrophages and preserves axons in mice with MOG peptide EAE. J. Neurosci. 34, 8175–8185 (2014).
Kim, R. Y. et al. Astrocyte CCL2 sustains immune cell infiltration in chronic experimental autoimmune encephalomyelitis. J. Neuroimmunol. 274, 53–61 (2014).
Locatelli, G. et al. Mononuclear phagocytes locally specify and adapt their phenotype in a multiple sclerosis model. Nat. Neurosci. 21, 1196–1208 (2018).
Mills Ko, E. et al. Deletion of astroglial CXCL10 delays clinical onset but does not affect progressive axon loss in a murine autoimmune multiple sclerosis model. J. Neuroinflammation 11, 105 (2014).
Krumbholz, M. et al. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain 129, 200–211 (2006).
Wang, X., Haroon, F., Karray, S., Martina, D. & Schluter, D. Astrocytic Fas ligand expression is required to induce T-cell apoptosis and recovery from experimental autoimmune encephalomyelitis. Eur. J. Immunol. 43, 115–124 (2013).
Becher, B., Tugues, S. & Greter, M. GM-CSF: from growth factor to central mediator of tissue inflammation. Immunity 45, 963–973 (2016).
Croxford, A. L. et al. The cytokine GM-CSF drives the inflammatory signature of CCR2+monocytes and licenses autoimmunity. Immun. 43, 502–514 (2015).
Komuczki, J. et al. Fate-mapping of GM-CSF expression identifies a discrete subset of inflammation-driving T helper cells regulated by cytokines IL-23 and IL-1β. Immunity 50, 1289–1304 (2019).
Wicks, I. P. & Roberts, A. W. Targeting GM-CSF in inflammatory diseases. Nat. Rev. Rheumatol. 12, 37–48 (2016).
Gutiérrez-Vázquez, C. & Quintana, F. J. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity 48, 19–33 (2018).
Wheeler, M. A., Rothhammer, V. & Quintana, F. J. Control of immune-mediated pathology via the aryl hydrocarbon receptor. J. Biol. Chem. 292, 12383–12389 (2017).
Rothhammer, V. & Quintana, F. J. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 19, 184–197 (2019).
Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).
Scheper, W. & Hoozemans, J. J. M. The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol. 130, 315–331 (2015).
Hetz, C., Zhang, K. & Kaufman, R. J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 21, 421–438 (2020).
Smith, H. L. et al. Astrocyte unfolded protein response induces a specific reactivity state that causes non-cell-autonomous neuronal degeneration. Neuron 105, 855–866.e855 (2020).
Alaamery, M. et al. Role of sphingolipid metabolism in neurodegeneration. J. Neurochem. 158, 25–35 (2021).
Brinkmann, V. et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 9, 883–897 (2010).
Choi, J. W. et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc. Natl Acad. Sci. USA 108, 751–756 (2011).
Rothhammer, V. et al. Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc. Natl Acad. Sci. USA 114, 2012–2017 (2017).
Zhang, W. et al. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 178, 176–189.e115 (2019).
Janke, R., Dodson, A. E. & Rine, J. Metabolism and epigenetics. Annu. Rev. Cell Dev. Biol. 31, 473–496 (2015).
Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012).
Huynh, J. L. & Casaccia, P. Epigenetic mechanisms in multiple sclerosis: implications for pathogenesis and treatment. Lancet Neurol. 12, 195–206 (2013).
Huynh, J. L. et al. Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nat. Neurosci. 17, 121–130 (2014).
Li, X., Xiao, B. & Chen, X.-S. DNA methylation: a new player in multiple sclerosis. Mol. Neurobiol. 54, 4049–4059 (2017).
Fan, G. DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132, 3345–3356 (2005).
Hatada, I. et al. Astrocyte-specific genes are generally demethylated in neural precursor cells prior to astrocytic differentiation. PLoS ONE 3, e3189 (2008).
Katsuoka, F. & Yamamoto, M. Small Maf proteins (MafF, MafG, MafK): history, structure and function. Gene 586, 197–205 (2016).
El-Behi, M. et al. The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat. Immunol. 12, 568–575 (2011).
Codarri, L. et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat. Immunol. 12, 560–567 (2011).
Long, J. M. & Holtzman, D. M. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179, 312–339 (2019).
Polanco, J. C. et al. Amyloid-beta and tau complexity — towards improved biomarkers and targeted therapies. Nat. Rev. Neurol. 14, 22–39 (2018).
Heneka, M. T. et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388–405 (2015).
Itagaki, S., McGeer, P. L., Akiyama, H., Zhu, S. & Selkoe, D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J. Neuroimmunol. 24, 173–182 (1989).
Nalivaeva, N. N., Beckett, C., Belyaev, N. D. & Turner, A. J. Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer’s disease? J. Neurochem. 120, 167–185 (2012).
Yan, P. et al. Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J. Biol. Chem. 281, 24566–24574 (2006).
Yin, K.-J. et al. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J. Neurosci. 26, 10939–10948 (2006).
Lesne, S. et al. Transforming growth factor-beta 1 potentiates amyloid-beta generation in astrocytes and in transgenic mice. J. Biol. Chem. 278, 18408–18418 (2003).
Leuba, G. et al. Neuronal and nonneuronal quantitative BACE immunocytochemical expression in the entorhinohippocampal and frontal regions in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 19, 171–183 (2005).
Blasko, I. et al. Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Aβ1-40 and Aβ1-42 by human astrocytes. Neurobiol. Dis. 7, 682–689 (2000).
Zhao, J., O’Connor, T. & Vassar, R. The contribution of activated astrocytes to Aβ production: implications for Alzheimer’s disease pathogenesis. J. Neuroinflammation 8, 150 (2011).
Hur, J. Y. et al. The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease. Nature 586, 735–740 (2020).
Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 e1217 (2017).
Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581.e569 (2017).
Meldrum, B. S. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J. Nutr. 130, 1007S–1015S (2000).
Hynd, M. R., Scott, H. L. & Dodd, P. R. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochem. Int. 45, 583–595 (2004).
Masliah, E., Alford, M., DeTeresa, R., Mallory, M. & Hansen, L. Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann. Neurol. 40, 759–766 (1996).
Mookherjee, P. et al. GLT-1 loss accelerates cognitive deficit onset in an Alzheimer’s disease animal model. J. Alzheimer’s Dis. 26, 447–455 (2011).
Matos, M. et al. Astrocytic adenosine A2A receptors control the amyloid-beta peptide-induced decrease of glutamate uptake. J. Alzheimers Dis. 31, 555–567 (2012).
Huang, S. et al. Astrocytic glutamatergic transporters are involved in Aβ-induced synaptic dysfunction. Brain Res. 1678, 129–137 (2018).
Liang, Z., Valla, J., Sefidvash-Hockley, S., Rogers, J. & Li, R. Effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from cortex of Alzheimer’s disease patients. J. Neurochem. 80, 807–814 (2002).
Hefendehl, J. K. et al. Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging. Nat. Commun. 7, 13441 (2016).
Rothstein, J. D. et al. β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73–77 (2005).
Abramov, A. Y., Canevari, L. & Duchen, M. R. Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J. Neurosci. 23, 5088–5095 (2003).
Lee, L., Kosuri, P. & Arancio, O. Picomolar amyloid-β peptides enhance spontaneous astrocyte calcium transients. J. Alzheimers Dis. 38, 49–62 (2013).
Kuchibhotla, K. V., Lattarulo, C. R., Hyman, B. T. & Bacskai, B. J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009).
Samakashvili, S. et al. Analysis of chiral amino acids in cerebrospinal fluid samples linked to different stages of Alzheimer disease. Electrophoresis 32, 2757–2764 (2011).
Yoshiike, Y. et al. GABAA receptor-mediated acceleration of aging-associated memory decline in APP/PS1 mice and its pharmacological treatment by picrotoxin. PLoS ONE 3, e3029 (2008).
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C. C. & Bu, G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol. 15, 501–518 (2019).
Mahley, R. W., Weisgraber, K. H. & Huang, Y. Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J. Lipid Res. 50, S183–S188 (2009).
Kim, J., Basak, J. M. & Holtzman, D. M. The role of apolipoprotein E in Alzheimer’s disease. Neuron 63, 287–303 (2009).
Verghese, P. B., Castellano, J. M. & Holtzman, D. M. Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol. 10, 241–252 (2011).
Holtzman, D. M., Herz, J. & Bu, G. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006312 (2012).
Kanekiyo, T., Xu, H. & Bu, G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron 81, 740–754 (2014).
Thambisetty, M., Beason-Held, L., An, Y., Kraut, M. A. & Resnick, S. M. APOE ε4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch. Neurol. 67, 93–98 (2010).
Sheline, Y. I. et al. APOE4 Allele Disrupts Resting State fMRI connectivity in the absence of amyloid plaques or decreased CSF A 42. J. Neurosci. 30, 17035–17040 (2010).
Reiman, E. M. et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc. Natl Acad. Sci. USA 101, 284–289 (2004).
Methia, N. et al. ApoE deficiency compromises the blood brain barrier especially after injury. Mol. Med. 7, 810–815 (2001).
Hafezi-Moghadam, A., Thomas, K. L. & Wagner, D. D. ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage. Am. J. Physiol. Cell Physiol. 292, C1256–C1262 (2007).
Poewe, W. et al. Parkinson disease. Nat. Rev. Dis. Prim. 3, 17013 (2017).
Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18, 1091–1102 (2019).
Hirsch, E. C. & Hunot, S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 8, 382–397 (2009).
Damier, P., Hirsch, E. C., Zhang, P., Agid, Y. & Javoy-Agid, F. Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience 52, 1–6 (1993).
Ciesielska, A. et al. The impact of age and gender on the striatal astrocytes activation in murine model of Parkinson’s disease. Inflamm. Res. 58, 747–753 (2009).
Morales, I., Sanchez, A., Rodriguez-Sabate, C. & Rodriguez, M. The astrocytic response to the dopaminergic denervation of the striatum. J. Neurochem. 139, 81–95 (2016).
Saijo, K. et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137, 47–59 (2009).
Chan, C. S., Gertler, T. S. & Surmeier, D. J. Calcium homeostasis, selective vulnerability and Parkinson’s disease. Trends Neurosci. 32, 249–256 (2009).
Bates, G. P. et al. Huntington disease. Nat. Rev. Dis. Prim. 1, 15005 (2015).
Ghosh, R. & Tabrizi, S. J. Clinical features of Huntington’s disease. Adv. Exp. Med. Biol. 1049, 1–28 (2018).
Hebb, M. O., Denovan-Wright, E. M. & Robertson, H. A. Expression of the Huntington’s disease gene is regulated in astrocytes in the arcuate nucleus of the hypothalamus of postpartum rats. FASEB J. 13, 1099–1106 (1999).
Shin, J. Y. et al. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J. Cell Biol. 171, 1001–1012 (2005).
Bradford, J. et al. Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc. Natl Acad. Sci. USA 106, 22480–22485 (2009).
Wood, T. E. et al. Mutant huntingtin reduction in astrocytes slows disease progression in the BACHD conditional Huntington’s disease mouse model. Hum. Mol. Genet. 28, 487–500 (2019).
Al-Dalahmah, O. et al. Single-nucleus RNA-seq identifies Huntington disease astrocyte states. Acta Neuropathol. Commun. 8, 19 (2020).
Roth, B. L. DREADDs for neuroscientists. Neuron 89, 683–694 (2016).
Jiang, R., Diaz-Castro, B., Looger, L. L. & Khakh, B. S. Dysfunctional calcium and glutamate signaling in striatal astrocytes from Huntington’s disease model mice. J. Neurosci. 36, 3453–3470 (2016).
Mochel, F. & Haller, R. G. Energy deficit in Huntington disease: why it matters. J. Clin. Invest. 121, 493–499 (2011).
Manoharan, S. et al. The role of reactive oxygen species in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: a mini review. Oxid. Med. Cell Longev. 2016, 8590578 (2016).
Kumar, A. & Ratan, R. R. Oxidative stress and Huntington’s disease: the good, the bad, and the ugly. J. Huntingtons Dis. 5, 217–237 (2016).
Leenders, K. L., Frackowiak, R. S., Quinn, N. & Marsden, C. D. Brain energy metabolism and dopaminergic function in Huntington’s disease measured in vivo using positron emission tomography. Mov. Disord. 1, 69–77 (1986).
Kuwert, T. et al. Cortical and subcortical glucose consumption measured by PET in patients with Huntington’s disease. Brain 113, 1405–1423 (1990).
May, J. M., Qu, Z. C. & Mendiratta, S. Protection and recycling of α-tocopherol in human erythrocytes by intracellular ascorbic acid. Arch. Biochem. Biophys. 349, 281–289 (1998).
Rebec, G. V., Barton, S. J. & Ennis, M. D. Dysregulation of ascorbate release in the striatum of behaving mice expressing the Huntington’s disease gene. J. Neurosci. 22, RC202 (2002).
Rebec, G. V., Barton, S. J., Marseilles, A. M. & Collins, K. Ascorbate treatment attenuates the Huntington behavioral phenotype in mice. Neuroreport 14, 1263–1265 (2003).
Rebec, G. V., Conroy, S. K. & Barton, S. J. Hyperactive striatal neurons in symptomatic Huntington R6/2 mice: variations with behavioral state and repeated ascorbate treatment. Neuroscience 137, 327–336 (2006).
Schonfeld, P. & Reiser, G. Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain. J. Cereb. Blood Flow. Metab. 33, 1493–1499 (2013).
Barber, C. N. & Raben, D. M. Lipid metabolism crosstalk in the brain: glia and neurons. Front.Cell. Neurosci. 13, 212 (2019).
Polyzos, A. et al. Mitochondrial targeting of XJB-5-131 attenuates or improves pathophysiology in HdhQ150 animals with well-developed disease phenotypes. Hum. Mol. Genet. 25, 1792–1802 (2016).
Bostan, A. C. & Strick, P. L. The basal ganglia and the cerebellum: nodes in an integrated network. Nat. Rev. Neurosci. 19, 338–350 (2018).
Kreitzer, A. C. & Malenka, R. C. Striatal plasticity and basal ganglia circuit function. Neuron 60, 543–554 (2008).
Liu, C., Goel, P. & Kaeser, P. S. Spatial and temporal scales of dopamine transmission. Nat. Rev. Neurosci. 22, 345–358 (2021).
Horga, G. & Abi-Dargham, A. An integrative framework for perceptual disturbances in psychosis. Nat. Rev. Neurosci. 20, 763–778 (2019).
Russo, S. J. & Nestler, E. J. The brain reward circuitry in mood disorders. Nat. Rev. Neurosci. 14, 609–625 (2013).
Sanz, E. et al. Cell-type-specific isolation of ribosome-associated mRNA from complex tissues. Proc. Natl Acad. Sci. USA 106, 13939–13944 (2009).
Zhang, Y. V., Ormerod, K. G. & Littleton, J. T. Astrocyte Ca2+ influx negatively regulates neuronal activity. eNeuro 4, ENEURO.0340-16.2017 (2017).
Lee, J. H. et al. Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature 590, 612–617 (2021). Groundbreaking study reporting that astrocytes, not microglia, are primarily responsible for activity-induced synaptic pruning controlling memory in the adult hippocampus.
Nguyen, P. T. et al. Microglial remodeling of the extracellular matrix promotes synapse plasticity. Cell 182, 388–403.e315 (2020).
Vainchtein, I. D. et al. Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 359, 1269–1273 (2018).
Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).
Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).
Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).
Yilmaz, M. et al. Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice. Nat. Neurosci. 24, 214–224 (2021).
Pfau, M. L., Menard, C. & Russo, S. J. Inflammatory mediators in mood disorders: therapeutic opportunities. Annu. Rev. Pharmacol. Toxicol. 58, 411–428 (2018).
Hodes, G. E., Kana, V., Menard, C., Merad, M. & Russo, S. J. Neuroimmune mechanisms of depression. Nat. Neurosci. 18, 1386–1393 (2015).
Fan, K. Q. et al. Stress-induced metabolic disorder in peripheral CD4+ T cells leads to anxiety-like behavior. Cell 179, 864–879.e819 (2019).
Kol, A. et al. Astrocytes contribute to remote memory formation by modulating hippocampal-cortical communication during learning. Nat. Neurosci. 23, 1229–1239 (2020).
Ii Timberlake, M. & Dwivedi, Y. Linking unfolded protein response to inflammation and depression: potential pathologic and therapeutic implications. Mol. Psychiatry 24, 987–994 (2019).
Cruz-Pereira, J. S. et al. Depression’s unholy trinity: dysregulated stress, immunity, and the microbiome. Annu. Rev. Psychol. 71, 49–78 (2020).
Leng, L. et al. Menin deficiency leads to depressive-like behaviors in mice by modulating astrocyte-mediated neuroinflammation. Neuron 100, 551–563.e557 (2018).
DiSabato, D. J. et al. Interleukin-1 receptor on hippocampal neurons drives social withdrawal and cognitive deficits after chronic social stress. Mol. Psychiatry 26, 4770–4782 (2021).
Zhang, F., Lin, Y. A., Kannan, S. & Kannan, R. M. Targeting specific cells in the brain with nanomedicines for CNS therapies. J. Control. Rel. 240, 212–226 (2016).
Wang, Y. C. et al. Sustained intraspinal delivery of neurotrophic factor encapsulated in biodegradable nanoparticles following contusive spinal cord injury. Biomaterials 29, 4546–4553 (2008).
Nance, E. et al. Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury. J. Control. Rel. 214, 112–120 (2015).
Terstappen, G. C., Meyer, A. H., Bell, R. D. & Zhang, W. Strategies for delivering therapeutics across the blood-brain barrier. Nat. Rev. Drug Discov. 20, 362–383 (2021).
Venier, R. E. & Igdoura, S. A. Miglustat as a therapeutic agent: prospects and caveats. J. Med. Genet. 49, 591–597 (2012).
Peterschmitt, M. J. et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of oral venglustat in healthy volunteers. Clin. Pharmacol. Drug Dev. 10, 86–98 (2021).
Arun, S., Liu, L. & Donmez, G. Mitochondrial biology and neurological diseases. Curr. Neuropharmacol. 14, 143–154 (2016).
Witte, M. E., Mahad, D. J., Lassmann, H. & van Horssen, J. Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol. Med. 20, 179–187 (2014).
Giladi, A. et al. Dissecting cellular crosstalk by sequencing physically interacting cells. Nat. Biotechnol. 38, 629–637 (2020).
Pasqual, G. et al. Monitoring T cell-dendritic cell interactions in vivo by intercellular enzymatic labelling. Nature 553, 496–500 (2018).
Turczyk, B. M. et al. Spatial sequencing: a perspective. J. Biomol. Tech. 31, 44–46 (2020).
Cisse, M. et al. Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469, 47–52 (2011).
Nkiliza, A. et al. RNA-binding disturbances as a continuum from spinocerebellar ataxia type 2 to Parkinson disease. Neurobiol. Dis. 96, 312–322 (2016).
Chung, E. K., Chen, L. W., Chan, Y. S. & Yung, K. K. Downregulation of glial glutamate transporters after dopamine denervation in the striatum of 6-hydroxydopamine-lesioned rats. J. Comp. Neurol. 511, 421–437 (2008).
Chotibut, T. et al. Ceftriaxone reduces L-dopa-induced dyskinesia severity in 6-hydroxydopamine Parkinson’s disease model. Mov. Disord. 32, 1547–1556 (2017).
Zhang, Y. et al. Regulation of glutamate transporter trafficking by Nedd4-2 in a Parkinson’s disease model. Cell Death Dis. 8, e2574 (2017).
Khakh, B. S. & McCarthy, K. D. Astrocyte calcium signaling: from observations to functions and the challenges therein. Cold Spring Harb. Perspect. Biol. 7, a020404 (2015).
Lublin, F. et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 387, 1075–1084 (2016).
Kappos, L. et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 391, 1263–1273 (2018).
Grassi, S. et al. Sphingosine 1-phosphate receptors and metabolic enzymes as druggable targets for brain diseases. Front. Pharmacol. 10, 807 (2019).
Wei, Z. D. & Shetty, A. K. Treating Parkinson’s disease by astrocyte reprogramming: progress and challenges. Sci. Adv. 7, eabg3198 (2021).
Guo, Z. et al. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell 14, 188–202 (2014).
Qian, H. et al. Reversing a model of Parkinson’s disease with in situ converted nigral neurons. Nature 582, 550–556 (2020).
Zhou, H. et al. Glia-to-neuron conversion by CRISPR-CasRx alleviates symptoms of neurological disease in mice. Cell 181, 590–603.e516 (2020).
Xue, Y. et al. Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits. Cell 152, 82–96 (2013).
Xue, Y. et al. Sequential regulatory loops as key gatekeepers for neuronal reprogramming in human cells. Nat. Neurosci. 19, 807–815 (2016).
Wang, L. L. et al. Revisiting astrocyte to neuron conversion with lineage tracing in vivo. Cell 184, 5465–5481 (2021).
Blackshaw, S. et al. Ptbp1 deletion does not induce glia-to-neuron conversion in adult mouse retina and brain. bioRxiv https://doi.org/10.1101/2021.10.04.462784 (2021).
Needham, B. D., Kaddurah-Daouk, R. & Mazmanian, S. K. Gut microbial molecules in behavioural and neurodegenerative conditions. Nat. Rev. Neurosci. 21, 717–731 (2020).
Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480.e1412 (2016).
Aho, V. T. E. et al. Gut microbiota in Parkinson’s disease: temporal stability and relations to disease progression. EBioMedicine 44, 691–707 (2019).
Yang, D. et al. The role of the gut microbiota in the pathogenesis of Parkinson’s disease. Front. Neurol. 10, 1155 (2019).
Scott, B. M. et al. Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease. Nat. Med. 27, 1212–1222 (2021).
Charbonneau, M. R., Isabella, V. M., Li, N. & Kurtz, C. B. Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nat. Commun. 11, 1738 (2020).
Aggarwal, N., Breedon, A. M. E., Davis, C. M., Hwang, I. Y. & Chang, M. W. Engineering probiotics for therapeutic applications: recent examples and translational outlook. Curr. Opin. Biotechnol. 65, 171–179 (2020).
Deneen, B. et al. The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52, 953–968 (2006).
Hochstim, C., Deneen, B., Lukaszewicz, A., Zhou, Q. & Anderson, D. J. Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code. Cell 133, 510–522 (2008). An early report of transcriptional programmes that regionally specify the establishment of astrocyte subsets.
Molofsky, A. V. et al. Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature 509, 189–194 (2014). This work shows that spinal cord astrocytes exhibit dorsal–ventral heterogeneity, which dictates the patterning of sensory and motor neuron projections to the spinal cord.
Tsai, H. H. et al. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337, 358–362 (2012). Functional validation of regionally defined astrocyte subsets that contribute to the establishment of CNS domains.
Chai, H. et al. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95, 531–549.e539 (2017).
Khakh, B. S. & Deneen, B. The emerging nature of astrocyte diversity. Annu. Rev. Neurosci. 42, 187–207 (2019).
Mews, P. et al. Alcohol metabolism contributes to brain histone acetylation. Nature 574, 717–721 (2019).
Ayata, P. et al. Epigenetic regulation of brain region-specific microglia clearance activity. Nat. Neurosci. 21, 1049–1060 (2018).
Wendeln, A.-C. et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556, 332–338 (2018).
Baecher-Allan, C., Kaskow, B. J. & Weiner, H. L. Multiple sclerosis: mechanisms and immunotherapy. Neuron 97, 742–768 (2018).
Reich, D. S., Lucchinetti, C. F. & Calabresi, P. A. Multiple Sclerosis. N. Engl. J. Med. 378, 169–180 (2018).
Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 595–608 (2016).
Sevigny, J. et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).
Selkoe, D. J. Alzheimer disease and aducanumab: adjusting our approach. Nat. Rev. Neurol. 15, 365–366 (2019).
Gu, X. L. et al. Astrocytic expression of Parkinson’s disease-related A53T α-synuclein causes neurodegeneration in mice. Mol. Brain 3, 12 (2010).
Arzberger, T., Krampfl, K., Leimgruber, S. & Weindl, A. Changes of NMDA receptor subunit (NR1, NR2B) and glutamate transporter (GLT1) mRNA expression in Huntington’s disease–an in situ hybridization study. J. Neuropathol. Exp. Neurol. 56, 440–454 (1997).
Kofuji, P. & Newman, E. A. Potassium buffering in the central nervous system. Neuroscience 129, 1045–1056 (2004).
Guttenplan, K. A. W. et al. Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature 599, 102–107 (2021). A recent study reporting that long-chain saturated lipids are one mechanism of astrocyte-induced neurodegeneration.
Acknowledgements
Research in the Quintana lab is supported by grants NS102807, ES02530, ES029136, AI126880 and AI149699 from the NIH; RG4111A1 from the National Multiple Sclerosis Society (to F.J.Q.), and PA-1604-08459 from the International Progressive MS Alliance. H.-G.L. was supported by a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1A6A3A14039088). M.A.W. was supported by the NIH (1K99NS114111, F32NS101790), a training grant from the NIH and Dana-Farber Cancer Institute (T32CA207201), a travelling neuroscience fellowship from the Program in Interdisciplinary Neuroscience at Brigham and Women’s Hospital, and the Women’s Brain Initiative at Brigham and Women’s Hospital.
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Drug Discovery thanks Jason Plemel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Tripartite synapses
-
Bidirectional interactions established by astrocytes with pre- and post-synaptic nerve terminals.
- Excitotoxicity
-
Neuronal dysfunction and death caused by the accumulation of excess neurotransmitters, primarily glutamate, in synapses.
- Relapsing–remitting mutiple sclerosis
-
(RRMS). The most common phenotype of multiple sclerosis, which is characterized by relapses followed by periods of partial or complete recovery. Most patients with RRMS will eventually develop secondary progressive multiple sclerosis.
- Secondary progressive multiple sclerosis
-
(SPMS). A phase of multiple sclerosis characterized by the progressive, irreversible accumulation of neurological disability, which shows limited response to available therapies.
- Gut–brain axis
-
(GBA). Bidirectional communication between the gut microbiota and the brain.
- Astrocyte–neuron lactate shuttle
-
Mechanism by which lactate released by astrocytes from glycolysis is used as a metabolic substrate for neurons under normal physiological conditions.
- Designer receptors exclusively activated by designer drugs
-
(DREADDs). Widely used tool for selectively manipulating neuronal activity indirectly through G protein-coupled receptor (GPCR)-dependent signalling pathways.
- Medium spiny neuron
-
(MSN). Class of inhibitory GABAergic neurons that represents ~95% of the neuronal population in the mammalian striatum.
- Synaptic pruning
-
Neurodevelopmental process of eliminating neurons and synaptic connections in the brain.
- Photoactivatable Ca2+ uncaging
-
Covalent attachment of a photochemical group to a biomolecule to render it inert until light irradiation releases the bond. In the case of Ca2+ uncaging, the photochemical group is attached to a Ca2+ chelator, such as EGTA.
- Poly(lactic-co-glycolic acid) nanoparticles
-
(PLGA nanoparticles). FDA-approved biodegradable polymeric nanoparticle extensively used in drug delivery systems owing to its biocompatibility and low toxicity.
- Polyamidoamine dendrimers
-
(PAMAM dendrimers). A class of dendrimers, hyperbranched macromolecules with numerous functional amine groups on the surface.
Rights and permissions
About this article
Cite this article
Lee, HG., Wheeler, M.A. & Quintana, F.J. Function and therapeutic value of astrocytes in neurological diseases. Nat Rev Drug Discov 21, 339–358 (2022). https://doi.org/10.1038/s41573-022-00390-x
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41573-022-00390-x
This article is cited by
-
Hyperglycemia enhances brain susceptibility to lipopolysaccharide-induced neuroinflammation via astrocyte reprogramming
Journal of Neuroinflammation (2024)
-
A comprehensive exploration of astrocytes in migraine: a bibliometric and visual analysis
European Journal of Medical Research (2024)
-
The angiotensin II receptors type 1 and 2 modulate astrocytes and their crosstalk with microglia and neurons in an in vitro model of ischemic stroke
BMC Neuroscience (2024)
-
Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Signal Transduction and Targeted Therapy (2024)
-
Precision drug delivery to the central nervous system using engineered nanoparticles
Nature Reviews Materials (2024)