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

Nat Commun. 2015 Mar 23:6:6597. doi: 10.1038/ncomms7597.


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 Mg(2+) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Epilepsy / metabolism*
  • GABA Plasma Membrane Transport Proteins / metabolism*
  • Hippocampus / metabolism*
  • In Vitro Techniques
  • Male
  • Nerve Net / metabolism
  • Patch-Clamp Techniques
  • Pyramidal Cells / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / metabolism*
  • Synapses / metabolism*
  • gamma-Aminobutyric Acid / metabolism*


  • GABA Plasma Membrane Transport Proteins
  • Receptors, GABA-A
  • Slc6a1 protein, rat
  • gamma-Aminobutyric Acid