Chronic epileptogenic cellular alterations in the limbic system after status epilepticus

Status epilepticus (SE) is associated with both acute and permanent patholo gical sequellae. One common long term consequence of SE is the subsequent d evelopment of a chronic epileptic condition, with seizures frequently origi nating from and involving the limbic system. Following SE, many studies hav e demonstrated selective loss of neurons-within the hilar region of the den tate gyms, CA1 and CA3 pyramidal neurons. Selective loss of distinct subpop ulations of interneurons throughout the hippocampus is also frequently evid ent, although interneurons as a whole are selectively spared relative to pr incipal cells. Accompanying this loss of neurons are circuit rearrangements , the most widely studied being the sprouting of dentate granule cell (DGC) axons back onto the inner molecular layer of the dentate gyrus, termed mos sy fiber sprouting. Less studied are the receptor properties of the survivi ng neurons within the epileptic hippocampus following SE. DGCs in epileptic animals exhibit marked alterations in the functional and pharmacological p roperties of gamma-aminobutyric acid (GABA) receptors. DGCs have a signific antly elevated density of GABA(A) receptors in chronically epileptic animal s. In addition, the pharmacological properties of GABA, receptors in post-S E epileptic animals are quite different compared to controls. In particular , GABA(A) receptors in DGCs from epileptic animals show an enhanced sensiti vity to blockade by zinc, and a markedly altered sensitivity to modulation by benzodiazepines. These pharmacological differences may be due to a decre ased expression of alpha 1 subunits of the GABA(A) receptor relative to oth er a subunits in DGCs of post-SE epileptic animals. These GABA(A) receptor alterations precede the onset of spontaneous seizures in post-SE DGCs, and so are temporally positioned to contribute to the process of epileptogenesi s in the limbic system. The presence of zinc sensitive GABA receptors combi ned with the presence of zinc-containing "sprouted" mossy fiber terminals i nnervating the proximal dendrites of DGCs in the post-SE epileptic hippocam pus prompted the development of the hypothesis that repetitive activation o f the DG in the epileptic brain could result in the release of zine. This z inc in turn may diffuse to and block "epileptic" zinc-sensitive GABA(A) rec eptors in DGCs, leading to a catastrophic failure of inhibition and concomi tant enhanced seizure propensity in the post-SE epileptic limbic system.