Astrocytic GABA transporter GAT-1 dysfunction in experimental absence seizures

J Physiol. 2013 Feb 15;591(4):823-33. doi: 10.1113/jphysiol.2012.242016. Epub 2012 Oct 22.

Abstract

An enhanced tonic GABA(A) inhibition in the thalamus plays a crucial role in experimental absence seizures and has been attributed, on the basis of indirect evidence, to a dysfunction of the astrocytic GABA transporter-1 (GAT-1). Here, the GABA transporter current was directly investigated in thalamic astrocytes from a well-established genetic model of absence seizures, the genetic absence epilepsy rats from Strasbourg (GAERS), and its non-epileptic control (NEC) strain. We also characterized the novel form of GABAergic and glutamatergic astrocyte-to-neuron signalling by recording slow outward currents (SOCs) and slow inward currents (SICs), respectively, in thalamocortical (TC) neurons of both strains. In patch-clamped astrocytes, the GABA transporter current was abolished by combined application of the selective GAT-1 and GAT-3 blocker, NO711 (30 μm) and SNAP5114 (60 μm), respectively, to GAERS and NEC thalamic slices. NO711 alone significantly reduced (41%) the transporter current in NEC, but had no effect in GAERS. SNAP5114 alone reduced by half the GABA transporter current in NEC, whilst it abolished it in GAERS. SIC properties did not differ between GAERS and NEC TC neurons, whilst moderate changes in SOC amplitude and kinetics were observed. These data provide the first direct demonstration of a malfunction of the astrocytic thalamic GAT-1 transporter in absence epilepsy and support an abnormal astrocytic modulation of thalamic ambient GABA levels. Moreover, while the glutamatergic astrocyte-neuron signalling is unaltered in the GAERS thalamus, the changes in some properties of the GABAergic astrocyte-neuron signalling in this epileptic strain may contribute to the generation of absence seizures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / physiology*
  • Epilepsy, Absence / physiopathology*
  • Female
  • GABA Plasma Membrane Transport Proteins / physiology*
  • In Vitro Techniques
  • Male
  • Neurons / physiology
  • Rats
  • Thalamus / physiopathology*

Substances

  • GABA Plasma Membrane Transport Proteins
  • Slc6a1 protein, rat