Extracellular Glutamate: Functional Compartments Operate in Different Concentration Ranges

Abstract

Extracellular glutamate of glial origin modulates glial and neuronal glutamate release and synaptic plasticity. Estimates of the tonic basal concentration of extracellular glutamate range over three orders of magnitude (0.02–20 μM) depending on the technology employed to make the measurement. Based upon binding constants for glutamate receptors and transporters, this range of concentrations translates into distinct physiological and pathophysiological roles for extracellular glutamate. Here we speculate that the difference in glutamate measurements can be explained if there is patterned membrane surface expression of glutamate release and transporter sites creating extracellular subcompartments that vary in glutamate concentration and are preferentially sampled by different technologies.

Astroglial cradle in the life of the synapse

“…Astrocytes regulate extracellular glutamate concentration by balancing glutamate uptake through Na þ -dependent astroglia-specific glutamate transporters (SLC1A3/EAAT1 and SLC1A2/ EAAT2) and glutamate release mainly through the cysteine-glutamate exchanger or system Xc 2 (SLC7A11) [52,53]. These two types of transporters are differentially expressed in the astroglial membranes so that glutamate uptake dominates around the synaptic cleft, whereas cysteine-glutamate exchangers are concentrated in extra-synaptic regions.…”

“…B 369: 20130595 is kept at low nanomolar levels (that prevents desensitization of glutamate receptors) and a high density of glutamate transporters ascertains rapid clearance of glutamate upon synaptic transmission. Extra-synaptically, however, glutamate is maintained at low micromolar concentrations that provide for tonic modulation of synaptic transmission and plasticity through extra-synaptic metabotropic (and possibly NMDA) glutamate receptors [53]. Besides providing for glutamate clearance and controlling interstitial glutamate distribution, astrocytes maintain glutamatergic transmission through supplying neurons with glutamate precursor, glutamine.…”

Permanent dynamic transporter-mediated turnover of glutamate across the plasma membrane of presynaptic nerve terminals: arguments in favor and against

“…Thus, estimates of the basal concentration of glutamate within the extracellular space vary over three orders of magnitude, ranging from 0.02 to 30 μm, and depend on the methods of measurement (Herman and Jahr, 2007;Chefer et al, 2009;Moussawi et al, 2011). Estimates of ambient glutamate based on microdialysis measurements are approximately 100-fold higher than those based on electrophysiological measurements of tonic NMDA receptor activity (Suna et al, 2014).…”

“…Glutamate concentration in the synaptic cleft following action potential-mediated release exceeds 1 mm for < 10 ms and quickly returns to < 20 nm between release events due to glutamate uptake by neurons and glia (Dzubay and Jahr, 1999). The extracellular glutamate concentration that resulted from electrophysiological estimates of tissue slices in vitro was 0.02-0.1 μm, whereas in vivo measurements using microdialysis or voltammetry varied between 1 and 30 μm (Moussawi et al, 2011).…”

“…The existence of numerous nonlinear mechanisms makes the characterization of glutamate homeostasis in the synapses very difficult (Pendyam et al, 2012), and the concentration of glutamate in the central nervous system varies in dependence on the biological compartment being measured (Moussawi et al, 2011). Glutamate levels in cerebrospinal fluid are around 10 μm; intracellular glutamate concentrations in the brain are approximately 10 mm (Danbolt, 2001, for review;Featherstone and Shippy, 2008).…”