In adult rats, intraperitoneal administration of kainic acid, a glutamic acid analog and potent neurotoxin, induces persistent seizure activity that results in electrographic alterations and neuropathology that closely resemble human temporal lobe epilepsy. We used in situ hybridization to identify regions of altered glutamate and GABAA receptor gene expression following kainate-induced status epilepticus. In the CA3/CA4 area, the hippocampal region most vulnerable to neurodegeneration after kainate acid treatment, expression of GluR2 (the AMPA/kainate receptor subunit that limits Ca2+ permeability) and GluR3 was decreased markedly at 12 and 24 hr, times preceding neurodegeneration. These findings raise the possibility that increased formation of Ca(2+)-permeable AMPA/kainate receptors in the CA3/CA4 area may enhance glutamate pathogenicity. Expression of the GABAA alpha 1, subunit was also reduced, indicating a possible decrease in inhibitory transmission, which would also enhance excitotoxicity. GluR1 and NR1 expression was not significantly changed. In the dentate gyrus, a region resistant to neurodegeneration, concomitant increases in GluR2 and GluR3 expression were observed; GluR1, NR1, and GABAA alpha 1 mRNAs were not detectably altered. Analysis of emulsion-dipped sections revealed that the changes in GluR2, GluR3, and GABAA alpha 1 expression represented changes in mRNA content per neuron and were specific to pyramidal cells of the CA3/CA4 area and to granule cells of the dentate gyrus. These findings indicate that kainate seizures modify hippocampal glutamate and GABAA receptor expression in a cell-specific manner. Timing of the changes in glutamate and GABAA receptor mRNAs indicates that these changes may play a causal role in hippocampal neuronal cell loss following kainate-induced seizures.
Seizures in adult rats result in long-term deficits in learning and memory, as well as an enhanced susceptibility to further seizures. In contrast, fewer lasting changes have been found following seizures in rats younger than 20 days old. This age-dependency could be due to differing amounts of hippocampal neuronal damage produced by seizures at different ages. To determine if there is an early developmental resistance to seizure-induced hippocampal damage, we compared the effects of kainic acid (KA)-induced status epilepticus and amygdala kindling on hippocampal dentate gyrus anatomy and electrophysiology, in immature (16 day old) and adult rats. In adult rats, KA status epilepticus resulted in numerous silver-stained degenerating dentate hilar neurons, pyramidal cells in fields CA1 and CA3, and marked numerical reductions in CA3c pyramidal neuron counts (-57%) in separate rats. Two weeks following the last kindled seizure, some, but significantly less, CA3c pyramidal cell loss was observed (-26%). Both KA status epilepticus and kindling in duced mossy-fiber sprouting, as evidenced by ectopic Timm staining in supragranular layers of the dentate gyrus. In hippocampal slices from adult rats, paired-pulse stimulation of perforant path axons revealed a persistent enhancement of dentate granule-cell inhibition following KA status epilepticus or kindling. While seizures induced by KA or kindling in 16-day-old rats were typically more severe than in adults, the immature hippocampus exhibited markedly less KA-induced cell loss (-22%), no kindling-induced loss, no detectable synaptic rearrangement, and no change in dentate inhibition. These results demonstrate that, in immature rats, neither severe KA-induced seizures nor repeated kindled seizures produce the kind of hippocampal damage and changes associated with even less severe seizures in adults. The lesser magnitude of seizure-induced hippocampal alterations in immature rats may explain their greater resistance to long-term effects of seizures on neuronal function, as well as future seizure susceptibility. Conversely, hippocampal neuron loss and altered synaptic physiology in adults may contribute to increased sensitivity to epileptogenic stimuli, spontaneous seizures, and behavioral deficits.
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