Relationship between tolerance to GABA A agonist and bursting properties in neocortical neurons during GABA-withdrawal syndrome

Abstract

The interruption of intracortical, chronic GABA infusion is known to give rise to ‘GABA withdrawal syndrome’ (GWS) consisting of electroencephalographic paroxysmal focal activities, associated with behavioral epileptic signs. Neocortical slices were obtained from rats presenting the GWS (GWS slices), and intracellular recordings were performed in the vicinity of the γ-aminobutyric acid (GABA)-infused site. Electrical stimulation of the underlying white matter induced paroxysmal depolarization shifts (PDSs) in virtually all neurons. Bath-applied GABA (1–10 μM) had no effect on these neurons, while the same dose range was found effective in blocking action potentials in saline-infused cortex slices obtained from control rats. In the GWS slices a population of neurons presented, in addition to synaptically induced PDSs, voltage-dependent and cobalt-sensitive PDSs and burst of action potentials induced by depolarizing current injections. These intrinsic bursting neurons were unresponsive to high doses of GABA (100 μM). Dose-response curves of isoguvacine, a specific GABA A agonist, showed a shift to the right for the intrinsic bursting cells whatever the parameter measured (depolarization or conductance increase): the ED 50 was 50–100 times higher for intrinsic bursting cells than for other non-intrinsic bursting cells, thus indicating that intrinsic bursting cells are tolerant to GABA A agonist. This tolerance may result from a decreased number of receptors or from a change in their properties as a consequence of the previous prolonged GABA infusion. The decreased in the GABA efficacy could lead to disinhibition and could thus give the appearance of epileptic events.