Document Type
Article
Publication Date
10-2023
Publisher
Nature Publishing Group
Source Publication
Nature
Source ISSN
0028-0836
Original Item ID
DOI: 10.1038/s41586-023-06502-w
Abstract
Multimodal astrocyte–neuron communications govern brain circuitry assembly and function. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+-dependent exocytosis similar to neurons. However, the existence of this mechanism has been questioned owing to inconsistent data and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes and using molecular, bioinformatic and imaging approaches, together with cell-specific genetic tools that interfere with glutamate exocytosis in vivo. By analysing existing single-cell RNA-sequencing databases and our patch-seq data, we identified nine molecularly distinct clusters of hippocampal astrocytes, among which we found a notable subpopulation that selectively expressed synaptic-like glutamate-release machinery and localized to discrete hippocampal sites. Using GluSnFR-based glutamate imaging in situ and in vivo, we identified a corresponding astrocyte subgroup that responds reliably to astrocyte-selective stimulations with subsecond glutamate release events at spatially precise hotspots, which were suppressed by astrocyte-targeted deletion of vesicular glutamate transporter 1 (VGLUT1). Furthermore, deletion of this transporter or its isoform VGLUT2 revealed specific contributions of glutamatergic astrocytes in cortico-hippocampal and nigrostriatal circuits during normal behaviour and pathological processes. By uncovering this atypical subpopulation of specialized astrocytes in the adult brain, we provide insights into the complex roles of astrocytes in central nervous system (CNS) physiology and diseases, and identify a potential therapeutic target.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
de Ceglia, Roberta; Ledonne, Ada; Litvin, David Gregory; Lind, Barbara Lykke; Carriero, Giovanni; Latagliata, Emanuele Claudio; Bindocci, Erika; Di Castro, Maria Amalia; Savtchouk, Iaroslav; Vitali, Ilaria; Ranjak, Anurag; Congiu, Mauro; Canonica, Tara; Wisden, William; Harris, Kenneth; Mameli, Manuel; Mercuri, Nicola; Telley, Ludovic; and Volterra, Andrea, "Specialized Astrocytes Mediate Glutamatergic Gliotransmission in the CNS" (2023). Biomedical Sciences Faculty Research and Publications. 264.
https://epublications.marquette.edu/biomedsci_fac/264
Comments
Published version. Nature, Vol. 622 (October 2023): 120-129. DOI. © 2023 Nature Publishing Group (Macmillan Publishers Limited). Used with permission.
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