The endoplasmic reticulum in perisynaptic astrocytic processes: shape, distribution and effect on calcium activity

Abstract

Neurotransmission triggers Ca2+ signals in perisynaptic astrocytic processes (PAPs). As most PAPs are below the diffraction limit, the presence of Ca2+ stores in PAPs, notably the endoplasmic reticulum (ER), is unclear. Here, we create 46 three dimensional meshes of hippocampal tripartite synapses reconstructed from electron microscopy. We find that 75% of PAPs contain some ER, as close as 72 nm to the synapse, and quantify its geometrical properties. To discern the effect of ER shape and distribution on Ca2+ activity, we implemented an algorithm that automatically redistributes the ER within the reconstructed PAP meshes, with constant ER and PAP shape. Reaction-diffusion simulations in those meshes reveal that Ca2+ signals in PAPs are shaped by a complex interplay between the clustering of Ca2+ channels, Ca2+ buffering, ER shape and distribution. This study, by detecting ER in PAPs and linking its spatial properties to Ca2+ activity, sheds new light on mechanisms regulating signal transmission at tripartite synapses.

Regulated exocytosis from astrocytes: a matter of vesicles?

“…Interestingly, a more recent paper reported and quantified the presence of organelles (ER and vesicular structures), potentially supporting Ca 2+ signaling and synaptic tuning, in leaflets (Aboufares El Alaoui et al, 2020). Although this latter study was performed in the cortex, it supports the finding in a recent work analyzing the presence of ER in PAPs from an existing VEM dataset (Calì et al, 2016) (Figure 1C, arrowheads) to simulate calcium dynamics (Denizot et al, 2021(Denizot et al, , 2022. Simulations support the presence of ER and SLMVs in PAPs (Manninen et al, 2018(Manninen et al, , 2023Linne et al, 2022).…”

“…Nevertheless, ultimate proof, to show them under electron microscopy in independent studies from different labs, is still missing. Few recent studies (Aboufares El Alaoui et al, 2020;Aten et al, 2022;Denizot et al, 2022) might play an important role in reopening a game that seemed closed a decade ago, by taking advantage of VEM. Moreover, an increasing number of labs acquiring high-resolution, large volumes, under EM, are sharing data with a larger community, a wonderful practice allowing the re-use of precious dataset for other purposes; this could be key to extend this quest to labs that are not directly working using electron microscopy.…”

“…An important criticism to the work, is the fact that all evidence is coming from the hippocampus, leading to speculations that SLMVs exocytosis might be a feature of a subgroup of astrocytes in this specific region. Interestingly, previous cited work of PAPs and others (Gavrilov et al, 2018;Denizot et al, 2022) have also analyzed hippocampal neuropil (Figure 1).…”