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Electrophoretic Delivery of γ-aminobutyric Acid GABA into Epileptic Focus Prevents Seizures in Mice
Published on: May 16, 2019
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Synaptic GABA release prevents GABA transporter type-1 reversal during excessive network activity
Leonid Savtchenko1, Maria Megalogeni1, Dmitri A Rusakov1
1UCL Institute of Neurology, Queen Square, London WC1N3BG, UK.
Nature Communications
|March 24, 2015
Summary
GABA transporters (GAT-1) do not reverse during intense brain activity, contrary to prevailing views. Synaptic release prevents non-vesicular GABA release, impacting epilepsy and GAT-1 therapies.
Area of Science:
- Neuroscience
- Neurophysiology
- Molecular Biology
Background:
- GABA transporters regulate extracellular GABA, influencing neuronal activity.
- A prevailing hypothesis suggests GAT-1 reversal causes non-vesicular GABA release during intense network activity.
- This has implications for therapies targeting GABA uptake.
Purpose of the Study:
- To investigate GAT-1 operation under varying network conditions.
- To test the hypothesis of GAT-1 reversal during intense neuronal activity.
- To assess the role of GAT-1 in physiological and pathological network states.
Main Methods:
- Combined a realistic kinetic model of GAT-1 with experimental measurements.
- Measured tonic GABAA receptor currents in ex vivo hippocampal slices.
- Utilized the 0 Mg(2+) model of epileptiform discharges in slices from healthy and epileptic rats.
Main Results:
- Simulations predicted that synaptic GABA release prevents GAT-1 reversal during network activity.
- Experimental data showed epileptiform activity correlated with increased synaptic GABA release.
- GAT-1 reversal was not observed during epileptiform activity.
Conclusions:
- Sustained efflux of GABA through GAT-1 is unlikely during physiological or pathological network activity.
- The prevailing view of GAT-1 reversal contributing to non-vesicular GABA release is challenged.
- Findings refine understanding of GABAergic signaling in brain function and dysfunction.
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