Stereological analysis of forebrain regions in kainate-treated epileptic rats

Patients and models of temporal lobe epilepsy display neuron loss in the hippocampal formation, but neuropathological changes also occur in other forebrain regions. We sought to evaluate the specificity and extent of volume loss of the major forebrain regions in epileptic rats months after kainate-induced status epilepticus. In systematic series of Nissl-stained sections, the areas of major forebrain regions were measured, and volumes were estimated using the Cavalieri principle. In some regions, the optical fractionator method was used to estimate neuron numbers. Most kainate-treated rats showed significant volume loss in the amygdala, olfactory cortex, and septal region, but others displayed different patterns, with significant loss only in the hippocampus or thalamus, for example. Average volume loss was most severe in the amygdala and olfactory cortex (82-83% of controls), especially the caudal parts of both regions. In the piriform cortex (including the endopiriform nucleus) of epileptic rats, an average of approximately one-third of Nissl-stained neurons and one-third of the GABAergic interneurons labeled by in situ hybridization for GAD67 mRNA were lost, and the extent of neuron loss was correlated with the extent of volume loss. Volumetric analysis of major forebrain regions was insensitive to specific neuron loss in subregions such as layer III of the entorhinal cortex and the hilus of the dentate gyrus. These findings provide quantitative evidence that kainate-treated rats tend to display extensive neuron and volume loss in the amygdala and olfactory cortex, although the patterns and extent of loss in forebrain regions vary considerably among individuals. In this status epilepticus-based model, extrahippocampal damage appears to be more extensive and hippocampal damage appears to be less extensive than that reported for patients with temporal lobe epilepsy.