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Fast synaptic communication uses diffusible transmitters whose spread is limited by uptake mechanisms. However, on the submicron-scale, the distance between two synapses, the extent of glutamate spread has so far remained difficult to measure. Here, we show that quantal glutamate release from individual hippocampal synapses activates extracellular iGluSnFr molecules at a distance of >1.5 μm. 2P-glutamate uncaging near spines further showed that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-Rs and N-methyl-D-aspartate (NMDA)-Rs respond to distant uncaging spots at approximately 800 and 2000 nm, respectively, when releasing the amount of glutamate contained in approximately five synaptic vesicles. The uncaging-induced remote activation of AMPA-Rs was facilitated by blocking glutamate transporters but only modestly decreased by elevating the recording temperature. When mimicking release from neighboring synapses by three simultaneous uncaging spots in the microenvironment of a spine, AMPA-R-mediated responses increased supra-additively. Interfering with extracellular glutamate diffusion through a glutamate scavenger system weakly reduced field synaptic responses but not the quantal amplitude. Together, our data suggest that the neuropil is more permissive to short-range spread of transmitter than suggested by theory, that multivesicular release could regularly coactivate nearest neighbor synapses and that on this scale glutamate buffering by transporters primarily limits the spread of transmitter and allows for cooperative glutamate signaling in extracellular microdomains. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail:


E A Matthews, W Sun, S M McMahon, M Doengi, L Halka, S Anders, J A Müller, P Steinlein, N S Vana, G van Dyk, J Pitsch, A J Becker, A Pfeifer, E T Kavalali, A Lamprecht, C Henneberger, V Stein, S Schoch, D Dietrich. Optical analysis of glutamate spread in the neuropil. Cerebral cortex (New York, N.Y. : 1991). 2022 Aug 22;32(17):3669-3689

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PMID: 35059716

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