IN CONTRAST TO KINDLED SEIZURES, THE FREQUENCY OF SPONTANEOUS EPILEPSY IN THE LIMBIC STATUS MODEL CORRELATES WITH GREATER ABERRANT FASCIA-DENTATA EXCITATORY AND INHIBITORY AXON SPROUTING, AND INCREASED STAINING FOR N-METHYL-D-ASPARTATE, AMPA AND GABA(A) RECEPTORS

This study determined whether there were differences in hippocampal ne uron loss and synaptic plasticity by comparing rats with spontaneous e pilepsy after limbic status epilepticus and animals with a similar fre quency of kindled seizures. At the University of Virginia, Sprague-Daw ley rats were implanted with bilateral ventral hippocampal electrodes and treated as follows; no stimulation (electrode controls; n=5): hipp ocampal stimulation without status (stimulation controls; n=5); and li mbic status from continuous hippocampal stimulation (n=12). The limbic status group were electrographically monitored for a minimum of four weeks. Four rats had no recorded chronic seizures (status controls), a nd all three control groups showed no differences in hippocampal patho logy and were therefore incorporated into a single group (controls). E ight limbic status animals eventually developed chronic epilepsy (spon taneous seizures) and an additional eight rats were kindled to a simil ar number and frequency of stage 5 seizures (kindled) as the spontaneo us seizures group. At the University of California (UCLA) the hippocam pi were processed for: (i) Nissl stain for densitometric neuron counts ; (ii) neo-Timm's histochemistry for messy fiber sprouting; and (iii) immunocytochemical staining for glutamate decarboxylase, N-methyl-D-as partate receptor subunit 2, AMPA receptor subunit 1 and the GABA(A) re ceptor. In the fascia dentata inner and outer molecular layers the neo -Timm's stain and immunoreactivity was quantified as gray values using computer image analysis techniques. Statistically significant results (P<0.05) showed the following. Compared to controls and kindled anima ls, rats with spontaneous seizures had: (i) lower neuron counts for th e fascia dentata hilus, CA3 and CA1 stratum pyramidale; (ii) greater s upragranular inner molecular layer messy fiber staining; and (iii) gre ater glutamate decarboxylase immunoreactivity in both molecular layers . Greater supragranular excitatory messy fiber and GABAergic axon spro uting correlated with: (i) increases in N-methyl-D-aspartate receptor subunit 2 inner molecular layer staining; (ii) more AMPA receptor subu nit 1 immunoreactivity in both molecular layers; and (iii) greater out er than inner molecular layer GABA(A) immunoreactivity. Furthermore, i n contrast to kindled animals, rats with spontaneous seizures showed t hat increasing seizure frequency per week and the total number of natu ral seizures positively correlated with greater Timm's and GABAergic a xon sprouting, and with increases in N-methyl-o-aspartate receptor sub unit 2 and AMPA receptor subunit 1 receptor staining. In this rat limb ic status model these findings indicate that chronic seizures are asso ciated with hippocampal neuron loss, reactive axon sprouting and incre ases in excitatory receptor plasticity that differ from rats with an e qual frequency of kindled seizures and controls. The hippocampal patho logical findings in the limbic status model are similar to those in hu mans with hippocampal sclerosis and mesial temporal lobe epilepsy, and support the hypothesis that synaptic reorganization of both excitator y and inhibitory systems in the fascia dentata is an important pathoph ysiological mechanism that probably contributes to or generates chroni c limbic seizures. (C) 1997 IBRO. Published by Elsevier Science Ltd.