Abstract
BackgroundGlutamate (Glu) and γ-aminobutyric acid (GABA) transporters play important roles in regulating neuronal activity. Glu is removed from the extracellular space dominantly by glial transporters. In contrast, GABA is mainly taken up by neurons. However, the glial GABA transporter subtypes share their localization with the Glu transporters and their expression is confined to the same subpopulation of astrocytes, raising the possibility of cooperation between Glu and GABA transport processes.Methodology/Principal FindingsHere we used diverse biological models both in vitro and in vivo to explore the interplay between these processes. We found that removal of Glu by astrocytic transporters triggers an elevation in the extracellular level of GABA. This coupling between excitatory and inhibitory signaling was found to be independent of Glu receptor-mediated depolarization, external presence of Ca2+ and glutamate decarboxylase activity. It was abolished in the presence of non-transportable blockers of glial Glu or GABA transporters, suggesting that the concerted action of these transporters underlies the process.Conclusions/SignificanceOur results suggest that activation of Glu transporters results in GABA release through reversal of glial GABA transporters. This transporter-mediated interplay represents a direct link between inhibitory and excitatory neurotransmission and may function as a negative feedback combating intense excitation in pathological conditions such as epilepsy or ischemia.
Highlights
Maintenance of the balance between c-aminobutyric acid (GABA) mediated inhibition and L-glutamate (Glu) mediated excitation is of crucial importance under normal and pathological conditions in the brain
We found that all Glu transporter substrates examined, but not non-transportable inhibitors were able to evoke GABA release
Glu receptor activation We presented several lines of evidence to support that Gluinduced GABA release does not involve Glu receptor-mediated depolarization
Summary
Maintenance of the balance between c-aminobutyric acid (GABA) mediated inhibition and L-glutamate (Glu) mediated excitation is of crucial importance under normal and pathological conditions in the brain. The steady control over the extracellular concentrations of Glu and GABA is crucial for cell viability. This task is performed by Glu and GABA transporters that remove the neurotransmitters from the extracellular space utilizing the downhill transport of Na+. In contrast to Glu, GABA is predominantly taken up by neurons through the GABA transporter subtype 1 (GAT-1). Little is known about the role of GAT subtypes localized to glial cells (GAT-2, GAT-3) despite their capability to markedly influence neuronal excitability [10] and the therapeutic potential of GAT-3 up-regulation in epilepsy [11,12]. Glutamate (Glu) and c-aminobutyric acid (GABA) transporters play important roles in regulating neuronal activity. The glial GABA transporter subtypes share their localization with the Glu transporters and their expression is confined to the same subpopulation of astrocytes, raising the possibility of cooperation between Glu and GABA transport processes
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