title: Synaptic GABA release prevents GABA transporter type-1 reversal during excessive network activity.
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 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.
authors: UCL Institute of Neurology, Queen Square, London WC1N3BG, UK.
authors: Leonid
authors: L
authors: Savtchenko
authors: UCL Institute of Neurology, Queen Square, London WC1N3BG, UK.
authors: Maria
authors: M
authors: Megalogeni
authors: UCL Institute of Neurology, Queen Square, London WC1N3BG, UK.
authors: Dmitri A
authors: DA
authors: Rusakov
authors: UCL Institute of Neurology, Queen Square, London WC1N3BG, UK.
authors: Matthew C
authors: MC
authors: Walker
authors: UCL Institute of Neurology, Queen Square, London WC1N3BG, UK.
authors: Ivan
authors: 0000000312666988
authors: I
authors: Pavlov
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism*; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009415:Nerve Net / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D011963:Receptors, GABA-A; C493415:Slc6a1 protein, rat; D005680:gamma-Aminobutyric Acid