Astrocytes as integrators of synaptic signalling

Astrocytes are present in the entire brain and each of them controls a specific brain territory and communicates with all cell types in its microenvironment, including the local vasculature. For a long time, it was assumed that the interactions of astrocytes with neighbouring elements primarily served metabolic and homeostatic functions. However, subsequent observations have also suggested that astrocyte have more sophisticated roles in brain function. This began with the discovery that astrocytes exhibit complex forms of Ca2+ excitation in response to synaptic activity and release gliotransmitters when the calcium signal reaches a threshold. This glio-transmission, in turn, can control individual synapses or large-scale synaptic networks.

To better understand the topology of this calcium signalling, we explored the morphology of astrocytes in 3D at the nanometric scale using a scanning electron microscope coupled with a focussed ion beam. In these images datasets we have first noticed that the arborization of the astrocyte comprises two distinct subdomains: the shafts and the leaflets that are convoluted structures that specifically interact with synapses. This subdomain contains minuscule ER saccules competent for protein translation and calcium release. Surprisingly, we observed that each leaflet was in contact with several synapses, and in some cases, leaflets were interconnected through gap junctions to form leaflets domains in contact with more than 100 synapses originating from distinct neuronal circuits. Further investigation using two photon microscopy revealed that synaptic activity induces specific Ca2+ activity in the leaflet and that this activity is cumulative. Indeed, 70% of the calcium waves had 2-to-10 spatially and/or temporally separated origins merging into large and long-lasting Ca2+ elevations, indicating an integration of synaptic inputs. 

Overall, our results provide insight into the cellular basis of many findings from the 21^st century indicating an active role of astrocytes in sensory processing, motor coordination, cognition and memory.  From this perspective, astrocyte leaflets may act as a conductor that coordinates synaptic activities occurring on different spatial-temporal scales via Ca2+ signals to execute computations that are distinct from those of neurons.

Reference :

Benoit L, Hristovska I, Liaudet N, Jouneau PH, Fertin A, de Ceglia R, Litvin DG, Di Castro MA, Jevtic M, Zalachoras I, Kikuchi T, Telley L, Bergami M, Usson Y, Hisatsune C, Mikoshiba K, Pernet-Gallay K, Volterra A. Astrocytes functionally integrate multiple synapses via specialized leaflet domains. Cell. 2025 Nov 13;188(23):6453-6472.

Karin Pernet Gallay est invitée par Yves Goldberg.