Specialized astrocytes mediate glutamatergic gliotransmission in the CNS

Roberta de Ceglia, Ada Ledonne, David Gregory Litvin, Barbara Lykke Lind, Giovanni Carriero, Emanuele Claudio Latagliata, Erika Bindocci, Maria Amalia Di Castro, Iaroslav Savtchouk, Ilaria Vitali, Anurag Ranjak, Mauro Congiu, Tara Canonica, William Wisden, Kenneth Harris, Manuel Mameli, Nicola Mercuri, Ludovic Telley () and Andrea Volterra ()
Additional contact information
Roberta de Ceglia: University of Lausanne
Ada Ledonne: University of Lausanne
David Gregory Litvin: University of Lausanne
Barbara Lykke Lind: University of Lausanne
Giovanni Carriero: University of Lausanne
Emanuele Claudio Latagliata: IRCCS Santa Lucia Foundation
Erika Bindocci: University of Lausanne
Maria Amalia Di Castro: Sapienza University
Iaroslav Savtchouk: University of Lausanne
Ilaria Vitali: University of Lausanne
Anurag Ranjak: University of Lausanne
Mauro Congiu: University of Lausanne
Tara Canonica: University of Lausanne
William Wisden: Imperial College London
Kenneth Harris: University College London
Manuel Mameli: University of Lausanne
Nicola Mercuri: IRCCS Santa Lucia Foundation
Ludovic Telley: University of Lausanne
Andrea Volterra: University of Lausanne

Nature, 2023, vol. 622, issue 7981, 120-129

Abstract: 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 conditions4–7. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+-dependent exocytosis similar to neurons8–10. However, the existence of this mechanism has been questioned11–13 owing to inconsistent data14–17 and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes18–21 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.

Date: 2023
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DOI: 10.1038/s41586-023-06502-w

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