Astrocytes functionally integrate multiple synapses via specialized leaflet domains
Astrocyte Ca<sup>2+</sup> dynamics control synaptic circuits and behavior, yet the underlying biology remains poorly understood. By combining volumetric high-resolution electron microscopy and two-photon Ca<sup>2+</sup> imaging, we characterize astrocyte leaflets that interface with synapses. These convoluted structures with ≤250 nm diameter originate from astrocytic shafts or cell bodies, contain minuscule endoplasmic reticulum saccules expressing IP<sub>3</sub> receptors but not mitochondria, and are often interconnected via gap junctions forming domains with cytosolic continuity. Leaflets enwrap 90% of synapses in clusters and only 10% individually. By fast imaging of astrocyte peripheral microvolumes, we identify leaflet-specific Ca<sup>2+</sup> events that were synaptically induced, IP<sub>3</sub>R1-mediated, and often displayed separate originations merging into large, long-lasting Ca<sup>2+</sup> elevations. Using combined axon-leaflet Ca<sup>2+</sup> imaging, we show that these complex events reflect integration of incoming inputs from different neurons. The astrocyte leaflet organization may thus coordinate, via Ca<sup>2+</sup> signals, multiple synapses and circuits active at different spatiotemporal scales, executing computations distinct from neurons.
Authors
- Matteo Bergami (ORCID: https://orcid.org/0000-0001-5525-5025)
- Maria Amalia Di Castro (ORCID: https://orcid.org/0000-0001-7480-1087)
- Arnold Fertin (ORCID: https://orcid.org/0000-0001-9563-9103)
- Ludovic Telley (ORCID: https://orcid.org/0000-0002-5041-1997)
- Toko Kikuchi (ORCID: https://orcid.org/0009-0008-6482-5964)
- Andrea Volterra (ORCID: https://orcid.org/0000-0003-1069-1602)
- Ioannis Zalachoras (ORCID: https://orcid.org/0000-0002-8113-3512)
- Yves Usson (ORCID: https://orcid.org/0000-0003-0242-191X)
- David Litvin (ORCID: https://orcid.org/0000-0001-7688-5894)
- Inès Hristovska (ORCID: https://orcid.org/0000-0003-4779-4103)
- Nicolas Liaudet
- Chihiro Hisatsune (ORCID: https://orcid.org/0000-0001-7811-7784)
- Milica Jevtic
- Roberta De Ceglia (ORCID: https://orcid.org/0000-0001-6264-677X)
- Lucas Benoit
- Pierre‐Henri Jouneau (ORCID: https://orcid.org/0000-0003-0350-4901)
- Karin Pernet-Gallay
- Katsuhiko Mikoshiba
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Institut polytechnique de Grenoble (FR)
- University of Geneva (CH)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- CEA Grenoble (FR)
- ShanghaiTech University (CN)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Grenoble Institute of Neurosciences (FR)
- Wyss Center for Bio and Neuroengineering (CH)
- Sapienza University of Rome (IT)
- Université Grenoble Alpes (FR)
- University of Lausanne (CH)
Publication Details
- Journal
- Cell
- Published
- 2025-09-24
- DOI
- https://doi.org/10.1016/j.cell.2025.08.036
- Citations
- 11
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 9.26