Preferential neuronal loss in layer III of the medial entorhinal cortex in rat models of temporal lobe epilepsy

Abstract

We recently described a pronounced neuronal loss in layer III of the entorhinal cortex (EC) in patients with intractable temporal lobe epilepsy (Du et al., 1993a). To explore the pathophysiology underlying this distinct neuropathology, we examined the EC in three established rat models of epilepsy using Nissl staining and parvalbumin immunohistochemistry. Adult male rats were either electrically stimulated in the ventral hippocampus for 90 min or injected with kainic acid or lithium/pilocarpine. Animals were observed for behavioral changes for up to 6 hr and were killed 24 hr or 4 weeks after the experimental treatments. At 24 hr, all animals that had exhibited a bout of acute status epilepticus showed a consistent pattern of neuronal loss in the EC in Nissl-stained sections. Neurodegeneration was most pronounced in layer III of the medial Ec at all dorsoventral levels. A few surviving neurons were frequently present in the lesioned area. An identical pattern of nerve cell loss was also seen in the EC of rats killed 4 weeks following the treatments. This lesion was completely prevented by an injection of diazepam and pentobarbital, given 1 hr after kainic acid administration. Immunohistochemistry demonstrated a relative resistance of parvalbumin-positive neurons in layer III of the medial EC. Taken together, these experiments indicate that prolonged seizures cause a preferential neuronal loss in layer III of the medial EC and that this lesion may be related to a pathological elevation of intracellular calcium ion concentrations.

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…TLE patients present with a pattern of brain damage known as Ammon's horn sclerosis (or mesial temporal sclerosis) that is typically characterized by neuronal loss in hippocampal CA1/CA3 subfields, dentate hilus, layer III of the medial EC, and amygdala (Gloor, 1991(Gloor, , 1997Houser, 1999;Du et al, 1993). Similar histopathological changes have been reported to occur in laboratory animals by injecting convulsant drugs such as pilocarpine or kainic acid, or by repetitive electrical stimulation of limbic pathways (Ben-Ari, 1985;Cavalheiro et al, 1991;Curia et al, 2008;Du et al, 1995). These experimental procedures induce an initial status epilepticus and cause 1-2 weeks later a chronic condition of recurrent limbic seizures.…”

Massive and Specific Dysregulation of Direct Cortical Input to the Hippocampus in Temporal Lobe Epilepsy

“…Selective lesion of layer III neurons in the entorhinal cortex using focal injections of aminooxyacetic acid has been shown to disrupt inhibitory processes in the hippocampus area CA1, leading to a hypothesis postulating that partial loss of layer III entorhinal cortical neurons may contribute to reductions in feedforward inhibition in area CA1, amplifying the temporoammonic pathway (Denslow et al, 2001). In patients with TLE and in pilocarpine animal models of epilepsy, cell loss in layer III of the entorhinal cortex has been shown (Du et al, 1993(Du et al, , 1995 (supplemental Fig. 3, available at www.jneurosci.org as supplemental material).…”

Astrocytes and Epilepsy

“…The entorhinal cortex is also reported to have neuronal loss with some gliosis, especially in layers three and to a lesser extent in layer two. 86 Studies with depth electrodes in the hippocampus of TLE patients show that seizure activity originates from such hippocampi, and especially from the most sclerotic regions within them. 87 How does this happen?…”

“…Abnormal epileptiform activity has been recorded from the EC region 91,92 and is reported to be the lead structure in the emergence of tonic discharges in mesial structures in a majority of patients with EC atrophy. 93,94 Some studies have reported neuronal loss and gliosis in superficial layers of the EC, 86 whereas others find no significant difference in neuronal densities in the EC of patients with and without hippocampal sclerosis. 95 However, gliosis was a common finding in the EC of sclerotic and nonsclerotic patients.…”