Mossy fiber zinc and temporal lobe epilepsy: Pathological association withaltered "epileptic" gamma-aminobutyric acid A receptors in dentate granulecells

Temporal lobe epilepsy is associated with circuit rearrangements within the hippocampus. Mossy fibers sprout and pathologically innervate the inner mo lecular layer of the dentate gyrus, providing a recurrent excitatory pathwa y not present in the control brain. In addition to releasing glutamate, the se recurrent collaterals also release zinc, which can accumulate in high co ncentrations in the extracellular space. Accompanying these dentate gyrus c ircuit rearrangements are alterations in the subunit expression patterns an d pharmacology of gamma-aminobutyric acid A (GABA(A)) receptors in dentate granule cells. In normal, control granule cells, GABA(A) receptors are zinc insensitive as a result of high levels of expression of the alpha 1 subuni t in these cells. In epileptic brain, expression of alpha 1 subunits decrea ses and expression of alpha 4 and delta subunits increases, leading to the assembly of GABA(A) receptors that are exquisitely zinc sensitive. This tem poral and spatial association of the expression of zinc-sensitive GABA(A) r eceptors and the emergence of a zinc-delivery system unique to the epilepti c hippocampus has led to the formulation of an hypothesis that suggests tha t zinc release during repetitive activation of the dentate gyrus may lead t o a catastrophic failure of inhibition under conditions mediating seizure i nitiation. This could contribute to the limbic hyperexcitability characteri stic of temporal lobe epilepsy.