Abstracts

Rationale: The hippocampus is highly sensitive to seizure-induced damage and is therefore a major region examined by numerous investigators whereas other limbic structures such as the retrosplenial and cingulate cortex; regions involved with seizure activity, memory, and other cognitive functions have received much less attention. One study showed that neuronal loss and volume reduction within the densely packed retrosplenial granular cortex (Rgb) occurred in response to pilocarpine-induced status epilepticus whereas the dysgranular adjacent retrosplenial region (Rdg) was spared. While examining the efficacy of retigabine, a selective K+ channel opener, on the seizure threshold and the associated hippocampal injury in adult rats at times following kainate (KA)-induced status epilepticus, obvious depletions of NeuN immunolabeling were observed in forebrain cortical structures.Methods: Kainate (KA) was administered to adult male rats (15 mg/kg, i.p.) to induce status epilepticus (SE). Cresyl violet staining and NeuN immunohistochemistry were used to assess the morphology and/or cell loss of the retrosplenial cortex and/or hippocampus at 3 and 28 days.Results: NeuN immunohistochemical labeling decreased markedly in Rgb and Rdg subregions in animals treated with KA relative to controls which corresponded to the same regions of GluR1 depletion at both earlier (3 d) and delayed (28 d) time points. Rats co-treated with retigabine exhibited the same pattern of NeuN loss but with increased delay. Despite NeuN depletion, Nissl staining revealed virtually no cortical neuronal loss and the hippocampal injury did not correlate with NeuN reductions. Horseradish peroxidase transport (HRP) studies illustrated previously that these neurons receive input from the cingulate cortex (Cg1 and Cg2) and project to adjacent Rdg neurons as well as basolateral amygdala and entorhinal cortex, significant circuitry of the limbic/ autonomic loop.Conclusions: Reduced fast synaptic transmission mediated by GluR1 subunits with simultaneous depletion of NeuN staining of nuclear elements in populations of limbic cortical neurons in the absence of cell loss may indicate a “circuitry break” due to lack of neurotransmission and transcriptional regulation within critical regions responsible for memory deficits and other cognitive comorbidities associated with sustained seizures.