Astrocytes Release ATP/ADP and Glutamate in Flashes Via Vesicular Exocytosis

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2024 Nov 23

PMID 39578520

Authors

Heng Li

Yuqing Zhao

Ruicheng Dai

Peiyao Geng

Danwei Weng

Wenting Wu

Fengting Yu

Rui Lin

Zhaofa Wu

Yulong Li

Minmin Luo

Affiliations

Soon will be listed here.

Abstract

Astrocytes regulate brain functions through gliotransmitters like ATP/ADP and glutamate, but their release patterns and mechanisms remain controversial. Here, we visualized ATP/ADP and glutamate response following astrocyte activation and investigated their mechanisms in vivo. Employing cOpn5-mediated optogenetic stimulation, genetically encoded fluorescent sensors, and two-photon imaging, we observed ATP/ADP released as temporally prolonged and spatially extended flashes that later converted to adenosine. This release occurs via Ca and VNUT-dependent vesicular exocytosis. Additionally, astrocytes also release glutamate in flashes through TeNT-sensitive exocytosis, independent of ATP/ADP release. ATP/ADP released by astrocytes triggers further ATP/ADP release from microglia through P2Y12- and VNUT-dependent mechanisms. VNUT in astrocytes and microglia also contributes to ATP/ADP release under LPS-induced brain inflammation. These findings establish Ca-dependent vesicular exocytosis as a key mode of action, reveal intricate astrocyte-microglia interactions, and suggest a role for gliotransmission in brain inflammation. Furthermore, the methodologies may provide valuable tools for deciphering glial physiology and pathophysiology.

References

Khakh B, Deneen B . The Emerging Nature of Astrocyte Diversity. Annu Rev Neurosci. 2019; 42:187-207. DOI: 10.1146/annurev-neuro-070918-050443. View

Chai H, Diaz-Castro B, Shigetomi E, Monte E, Christopher Octeau J, Yu X . Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence. Neuron. 2017; 95(3):531-549.e9. PMC: 5811312. DOI: 10.1016/j.neuron.2017.06.029. View

Vardjan N, Parpura V, Verkhratsky A, Zorec R . Gliocrine System: Astroglia as Secretory Cells of the CNS. Adv Exp Med Biol. 2019; 1175:93-115. PMC: 7190456. DOI: 10.1007/978-981-13-9913-8_4. View

Parpura V, Zorec R . Gliotransmission: Exocytotic release from astrocytes. Brain Res Rev. 2009; 63(1-2):83-92. PMC: 2862866. DOI: 10.1016/j.brainresrev.2009.11.008. View

Harada K, Kamiya T, Tsuboi T . Gliotransmitter Release from Astrocytes: Functional, Developmental, and Pathological Implications in the Brain. Front Neurosci. 2016; 9:499. PMC: 4709856. DOI: 10.3389/fnins.2015.00499. View

Shen W, Nikolic L, Meunier C, Pfrieger F, Audinat E . An autocrine purinergic signaling controls astrocyte-induced neuronal excitation. Sci Rep. 2017; 7(1):11280. PMC: 5595839. DOI: 10.1038/s41598-017-11793-x. View

Kofuji P, Araque A . Astrocytes and Behavior. Annu Rev Neurosci. 2021; 44:49-67. PMC: 8257756. DOI: 10.1146/annurev-neuro-101920-112225. View

Chen J, Tan Z, Zeng L, Zhang X, He Y, Gao W . Heterosynaptic long-term depression mediated by ATP released from astrocytes. Glia. 2012; 61(2):178-91. DOI: 10.1002/glia.22425. View

Brandebura A, Paumier A, Onur T, Allen N . Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders. Nat Rev Neurosci. 2022; 24(1):23-39. PMC: 10198620. DOI: 10.1038/s41583-022-00641-1. View

10.

Guthrie P, Knappenberger J, Segal M, Bennett M, Charles A, Kater S . ATP released from astrocytes mediates glial calcium waves. J Neurosci. 1999; 19(2):520-8. PMC: 6782195. View

11.

Duan S, Anderson C, Keung E, Chen Y, Chen Y, Swanson R . P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci. 2003; 23(4):1320-8. PMC: 6742264. View

12.

Zhang Z, Chen G, Zhou W, Song A, Xu T, Luo Q . Regulated ATP release from astrocytes through lysosome exocytosis. Nat Cell Biol. 2007; 9(8):945-53. DOI: 10.1038/ncb1620. View

13.

Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E . CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci. 2001; 4(7):702-10. DOI: 10.1038/89490. View

14.

Bazargani N, Attwell D . Astrocyte calcium signaling: the third wave. Nat Neurosci. 2016; 19(2):182-9. DOI: 10.1038/nn.4201. View

15.

Tan Z, Liu Y, Xi W, Lou H, Zhu L, Guo Z . Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons. Nat Commun. 2017; 8:13772. PMC: 5290168. DOI: 10.1038/ncomms13772. View

16.

Figueiredo M, Lane S, Stout Jr R, Liu B, Parpura V, Teschemacher A . Comparative analysis of optogenetic actuators in cultured astrocytes. Cell Calcium. 2014; 56(3):208-14. PMC: 4169180. DOI: 10.1016/j.ceca.2014.07.007. View

17.

Lalo U, Palygin O, Rasooli-Nejad S, Andrew J, Haydon P, Pankratov Y . Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLoS Biol. 2014; 12(1):e1001747. PMC: 3883644. DOI: 10.1371/journal.pbio.1001747. View

18.

Martin R, Bajo-Graneras R, Moratalla R, Perea G, Araque A . Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways. Science. 2015; 349(6249):730-4. DOI: 10.1126/science.aaa7945. View

19.

Noh K, Cho W, Lee B, Kim D, Kim Y, Park K . Cortical astrocytes modulate dominance behavior in male mice by regulating synaptic excitatory and inhibitory balance. Nat Neurosci. 2023; 26(9):1541-1554. DOI: 10.1038/s41593-023-01406-4. View

20.

Suadicani S, Iglesias R, Wang J, Dahl G, Spray D, Scemes E . ATP signaling is deficient in cultured Pannexin1-null mouse astrocytes. Glia. 2012; 60(7):1106-16. PMC: 3348971. DOI: 10.1002/glia.22338. View