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Critical Reviews™ in Neurobiology
Seizures Beget Seizures: The Quest for GABA as a Key Player
INMED, INSERM U 29, Parc Scientifique etTechnologique de Luminy, Marseille, France
Synapses mediated by γ-aminobutyric acid (GABA) A receptors are notoriously altered during periods of enhanced activity. Since a loss of inhibitory tone is a basic cause of seizures and epilepsies, it is important to determine the underlying mechanisms and the way this could be alleviated or at least reduced. Alterations of the intracellular content of chloride are thought to be a major player in the sequence of events that follow episodes of hyperactivity. In this review, I discuss these mechanisms both in the adult and developing brain, relying on studies in which chloride and GABAergic currents were measured by electrophysiological and imaging techniques. The main conclusion is that in adult systems, status epilepticus induces a complete re-organization of the networks, with cell death, axonal growth, and glutamatergic neosynapse formation leading to an increased glutamatergic drive. This, in turn, will decrease the threshold of seizure generation and thus contribute to seizure generation. In contrast, GABAergic synapses are not readily "plastic" as the lost interneurones and synapses are not replaced. Somatostatin-positive 0-LM Interneurons that innervate the dendrites of the principal cells in the hippocampus degenerate selectively, leading to a loss of the inhibitory drive in the dendrites, whereas somatic projecting basket cells and somatic inhibitory drives are relatively spared. This imbalance leads to a reduction of the inhibitory strength that is necessary but not sufficient to generate ongoing seizures. An additional important factor is the persistent increase of the intracellular chloride concentration that leads to a long-lasting shift in the depolarizing direction of the actions of GABA that will also contribute to seizure generation. In the developing brain, a major source of seizure generation is the depolarizing and often excitatory actions of GABA due to a higher intracellular chloride concentration ([Cl−]I) in immature neurons, a property that has been confirmed in all developing systems and animal species studied. As a consequence, immature GABAergic synapses will excite targets and facilitate the emergence of seizures, in keeping with the well-known higher incidence of seizures in the developing brain. Using a unique preparation with two intact hippocampi placed in a three-compartment chamber in vitro, we have provided direct evidence that seizures beget seizures and that GABA signaling plays a central role in this phenomenon. Indeed, recurrent seizures triggered in one hippocampus by a convulsive agent propagate to the other hippocampus and transform the naive hippocampus into one that generates seizures once disconnected from the other hippocampus. This transformation is conditioned by the occurrence during the seizures of high-frequency oscillations (40 Hz and above). Interestingly, these oscillations are only produced when N-methyl-D-aspartate (NMDA-) and GABA receptors are operative and not blocked in the naïve hippocampus. Therefore, GABA-receptor antagonists are pro-convulsive in the developing brain but, in fact, anti-epileptic. This paradoxical conclusion has quite a few clinical implications that are discussed.
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