Abstracts

In adult rats, a loss of GluR2 subunit expression and subsequent increases in AMPA receptor mediated Ca²⁺ currents were thought to enhance glutamate excitotoxicity after status epilepticus because, GluR2 protein is selectively decreased in vulnerable CA3 neurons before cell death. However, we now know that expression of AMPA receptors after status epilepticus depends upon the age of the animal and history of perinatal seizures as does the seizure-induced pattern of damage. We characterized maturational changes in AMPA receptor levels of the hippocampus with immunohistochemistry and westerns in rats and humans of adolescent and adult ages with and without a history of seizures. Kainic acid (KA) was used to induce a single episode of status epilepticus in rats on P13, P20 and P30 and two earlier episodes of KA seizures were induced on P6 and P9 in half of the animals. Parallel experiments were conducted in human resected hippocampus from several ages. In young P20 and P30 rats sensitive to CA1 damage GluR1 immunoreactivity was depleted in CA1 stratum pyramidale and stratum lucidum and only the morphologically healthy cells were labeled. At P30, GluR2 subunit expression was nearly absent in the healthy cells and highly upregulated within the injured CA1 neuronal population. A history of perinatal seizures prevented alterations in CA1 but not CA3. In humans, decreases, increases or sustained levels of the GluR2 subunit have been reported within sclerotic hippocampal regions but we found the discrepancies may be due to maturational differences. In a 28 yr old patient, GluR2 protein was increased in H1 neurons and decreased in H3, whereas GluR1 was sustained, increased or decreased depending on the area. The opposite was found in an older patient where GluR1 was nearly absent in surviving regions of the H1, however, GluR2 was sustained in adjacent sections. In H3, both GluR1 and GluR2 proteins were decreased in cell somata, GluR1 was increased in the neuropil and marked cell loss was noted. In a 6 yr old patient GluR2 was increased in H1 and decreased in H3 where cell loss was noted. There are age-dependent effects of seizures on AMPA receptor expression in rats and humans such that the non-selective and varied expression patterns of AMPA receptors do not support the original assumption that Ca²⁺ permeable AMPA receptors induce neuronal cell death. The particular history of seizures and antiepileptic protocols appear critical to the clinical outcome. Loss of both GluR1 and GluR2 in principal cells and an increase of GluR1 within interneurons may be a mechanism underlying seizure-induced tolerance. (Supported by New Jersey Neuroscience Institute)