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

Leonid Savtchenko, Maria Megalogeni, Dmitri A. Rusakov, Matthew C. Walker and Ivan Pavlov ()
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Leonid Savtchenko: UCL Institute of Neurology, Queen Square
Maria Megalogeni: UCL Institute of Neurology, Queen Square
Dmitri A. Rusakov: UCL Institute of Neurology, Queen Square
Matthew C. Walker: UCL Institute of Neurology, Queen Square
Ivan Pavlov: UCL Institute of Neurology, Queen Square

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7597

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DOI: 10.1038/ncomms7597

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