The multiple facets of gamma-aminobutyric acid dysfunction in epilepsy.
OBJECTIVE
The polarity of action of gamma-aminobutyric acid (GABA) changes from inhibition to excitation in the developing brain and in epilepsies. This review deals with recent observations concerning the mechanisms and clinical implications of the shift in GABA's activity from inhibition to excitation.


RESULTS
GABAergic synapses provide most transmitter-gated inhibition and are the targets of numerous clinically active agents, notably antiepileptic drugs. In a wide range of brain structures and species, GABAergic synapses are excitatory during maturation because of a higher concentration of intracellular chloride. These findings suggest that activation of GABA synapses will excite foetal neurones while inhibiting those of the mother. In epilepsies, recurrent seizures also lead to an accumulation of chloride and an excitatory action of GABA. These observations have major implications for clinical practice and research. They suggest that use of benzodiazepines by pregnant mothers may lead to deleterious consequences when they are taken during the period when GABA is the main excitatory transmitter. Because neuronal activity alters important cell functions, including migration and morphogenesis, aberrant excessive excitation may lead to profound deleterious consequences.


CONCLUSIONS
In several physiological and pathological conditions, activation of GABAergic synapses excites neurones instead of producing classical inhibition. This shift, which is due to an intracellular accumulation of chloride, has major consequences for both the operation of networks and the pathogenic effects of epilepsies. This is particularly important in the immature brain, where the excitatory actions of GABA are particularly prominent.
Ben-Ari
Yehezkel
Y
Institut de Neurobiologie de le Méditerranée, INSERM, Parc scientifique de Luminy, Marseilles, France. ben-ari@inmed.univ-mrs.fr
Holmes
Gregory L
GL
D001923:Brain Chemistry / Q000502:physiology*; D004827:Epilepsy / Q000503:physiopathology*; D006801:Humans; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D005680:gamma-Aminobutyric Acid