Local Efficacy of Glutamate Uptake Decreases with Synapse Size

Michel K Herde,Kirsten Bohmbach,Cátia Domingos,Natascha Vana,Joanna A Komorowska-Müller,Stefan Passlick,Inna Schwarz,Colin J Jackson,Dirk Dietrich,Martin K Schwarz,Christian Henneberger

doi:10.1016/j.celrep.2020.108182

Abstract

Synaptically released glutamate is largely cleared by glutamate transporters localized on perisynaptic astrocyte processes. Therefore, the substantial variability of astrocyte coverage of individual hippocampal synapses implies that the efficacy of local glutamate uptake and thus the spatial fidelity of synaptic transmission is synapse dependent. By visualization of sub-diffraction-limit perisynaptic astrocytic processes and adjacent postsynaptic spines, we show that, relative to their size, small spines display a stronger coverage by astroglial transporters than bigger neighboring spines. Similarly, glutamate transients evoked by synaptic stimulation are more sensitive to pharmacological inhibition of glutamate uptake at smaller spines, whose high-affinity N-methyl-D-aspartate receptors (NMDARs) are better shielded from remotely released glutamate. At small spines, glutamate-induced and NMDAR-dependent Ca2+ entry is also more strongly increased by uptake inhibition. These findings indicate that spine size inversely correlates with the efficacy of local glutamate uptake and thereby likely determines the probability of synaptic crosstalk.

Highlights

The uptake of released neurotransmitters is an essential mechanism in synaptic transmission and prevents excitotoxic effects of the neurotransmitter glutamate
Superresolved Visualization of Perisynaptic Astroglial Glutamate Transporters A quantitative assessment of the spatial relationship between glutamate transporters localized on perisynaptic astrocyte processes and synaptic spines requires high-resolution visualization of the spines and the leaf-like perisynaptic astrocyte processes, which can be as thin as 100–200 nm (Heller and Rusakov, 2015; Medvedev et al, 2014; Ventura and Harris, 1999)
In line with the notion that astroglial glutamate transporters mediate most of hippocampal glutamate uptake (Danbolt, 2001; Rose et al, 2018), GLT-1 labeling outlined EGFP-positive astrocyte processes

Summary

Introduction

The uptake of released neurotransmitters is an essential mechanism in synaptic transmission and prevents excitotoxic effects of the neurotransmitter glutamate. The physiological reduction of the coverage of neurons by astrocytes in the supraoptic nucleus during lactation is accompanied by a decreased uptake of synaptically released glutamate, which can increase the recruitment of presynaptic glutamate receptors (Oliet et al, 2001). A key model for studying synaptic transmission and plasticity, electron microscopy studies of the CA1 stratum radiatum revealed that only $40%–60% of synapses have astrocyte processes, which can be as thin as 100– 200 nm, directly apposed (Ventura and Harris, 1999; Witcher et al, 2007). The functional correlate of a difference in astrocytic coverage between postsynaptic spine types has remained largely unclear. It remains to be established which morphological aspects of astrocytic coverage are functionally relevant and for which biological processes

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Conclusion