TY - JOUR

T1 - Specialized astrocytes mediate glutamatergic gliotransmission in the CNS

AU - de Ceglia, Roberta

AU - Ledonne, Ada

AU - Litvin, David Gregory

AU - Lind, Barbara Lykke

AU - Carriero, Giovanni

AU - Latagliata, Emanuele Claudio

AU - Bindocci, Erika

AU - Di Castro, Maria Amalia

AU - Savtchouk, Iaroslav

AU - Vitali, Ilaria

AU - Ranjak, Anurag

AU - Congiu, Mauro

AU - Canonica, Tara

AU - Wisden, William

AU - Harris, Kenneth

AU - Mameli, Manuel

AU - Mercuri, Nicola

AU - Telley, Ludovic

AU - Volterra, Andrea

N1 - Publisher Copyright: © 2023, The Author(s).

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-023-06502-w

DO - 10.1038/s41586-023-06502-w

M3 - Journal article

C2 - 37674083

AN - SCOPUS:85169879166

VL - 622

SP - 120

EP - 129

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -