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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Leonid Savtchenko & Maria Megalogeni & Dmitri A. Rusakov & Matthew C. Walker & Ivan Pavlov, 2015. "Synaptic GABA release prevents GABA transporter type-1 reversal during excessive network activity," Nature Communications, Nature, vol. 6(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7597
    DOI: 10.1038/ncomms7597
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