Specialized astrocytes mediate glutamatergic gliotransmission in the CNS

de Ceglia, Roberta and Ledonne, Ada and Litvin, David Gregory and Lind, Barbara Lykke and Carriero, Giovanni and Latagliata, Emanuele Claudio and Bindocci, Erika and Di Castro, Maria Amalia and Savtchouk, Iaroslav and Vitali, Ilaria and Ranjak, Anurag and Congiu, Mauro and Canonica, Tara and Wisden, William and Harris, Kenneth and Mameli, Manuel and Mercuri, Nicola and Telley, Ludovic and Volterra, Andrea (2023) Specialized astrocytes mediate glutamatergic gliotransmission in the CNS. Nature, 622 (7981). pp. 120-129. ISSN 0028-0836

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Abstract

Multimodal astrocyte–neuron communications govern brain circuitry assembly and function1. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity2,3 of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions4,5,6,7. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+-dependent exocytosis similar to neurons8,9,10. However, the existence of this mechanism has been questioned11,12,13 owing to inconsistent data14,15,16,17 and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes18,19,20,21 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 imaging22 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.

Item Type: Article
Subjects: Open Research Librarians > Multidisciplinary
Depositing User: Unnamed user with email support@open.researchlibrarians.com
Date Deposited: 14 Nov 2023 07:25
Last Modified: 14 Nov 2023 07:25
URI: http://stm.e4journal.com/id/eprint/2088

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