Changes in AMPA receptor binding and subunit messenger RNA expression in hippocampus and cortex in the pentylenetetrazole-induced ‘kindling’ model of epilepsy

Abstract

‘Kindling’ is a phenomenon of epileptogenesis, which has been widely used as an experimental model of temporal lobe epilepsy. In the present study, we have examined the contribution of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptors and their subunits (GluR-A, -B, -C and -D) to the acquisition and maintenance of the kindled state in the pentylenetetrazole (PTZ)-induced ‘kindling’ mouse model, by using quantitative autoradiography and in situ hybridization. Region-specific increases in [ 3H]AMPA binding were seen in kindled animals in the CA3 region of hippocampus and in the temporal cortex 1 week after the last PTZ injection. At the same time, a significant decrease in the level of transcripts encoding the GluR-B and -C subunits was detected in the hippocampal CA1 region and dentate gyrus, suggestive of a higher proportion of Ca 2+-permeable AMPA receptors in these neurons. These changes did not persist 1 month after establishment of kindling, indicating a transient role of AMPA receptors in the acquisition of the kindled state. At 1 month after the last PTZ injection, an upregulation in [ 3H]AMPA binding appeared in the motor cortex and the basal ganglia of kindled animals, which is consistent with electrophysiological data showing hyperexcitability in the cortex of the PTZ-kindled animals at that time. Interestingly, an increase in mRNA for the GluR-B subunit appeared in the outer layers of motor and somatosensory cortices of the kindled animals 1 month after acquisition of the kindled state, possibly as part of a gene-regulated, compensatory mechanism against seizure susceptibility, since this change should give rise to a higher proportion of Ca 2+-impermeable AMPA receptors. These results support the evidence of a transient role of hippocampal AMPA receptors in the acquisition of the ‘kindling’ phenomenon and they also suggest an involvement of AMPA receptors in the maintenance of kindled state at least in two brain areas, cortex and basal ganglia.