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Synaptic GABA release prevents GABA transporter type-1 reversal during excessive network activity

L. Savtchenko,M. Megalogeni,D. Rusakov,M. Walker,I. Pavlov

Published 2015 in Nature Communications

ABSTRACT

GABA transporters control extracellular GABA, which regulates the key aspects of neuronal and network behaviour. A prevailing view is that modest neuronal depolarization results in GABA transporter type-1 (GAT-1) reversal causing non-vesicular GABA release into the extracellular space during intense network activity. This has important implications for GABA uptake-targeting therapies. Here we combined a realistic kinetic model of GAT-1 with experimental measurements of tonic GABAA receptor currents in ex vivo hippocampal slices to examine GAT-1 operation under varying network conditions. Our simulations predict that synaptic GABA release during network activity robustly prevents GAT-1 reversal. We test this in the 0 Mg2+ model of epileptiform discharges using slices from healthy and chronically epileptic rats and find that epileptiform activity is associated with increased synaptic GABA release and is not accompanied by GAT-1 reversal. We conclude that sustained efflux of GABA through GAT-1 is unlikely to occur during physiological or pathological network activity. Membrane depolarization during increased neuronal activity as seen during epilepsy has been suggested to easily reverse neuronal GABA transporters. Here the authors use modelling and experimental data and challenge this view by showing that synaptic GABA release during excessive neuronal firing averts reversal of GABA uptake.

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