Up-regulation of neuropeptide Y-Y2 receptors in an animal model of temporal lobe epilepsy

Receptor autoradiography with the Y-2, receptor ligand I-125-peptide YY3-36,,, and in situ hybridization were applied to investigate changes in neuropeptide tyrosine-Y-2, receptor expression after kainic acid-induced recurrent seizures in the rat hippocampus. In the strata oriens and radiatum of CAI to CA3, which are densely innervated by Y-2, receptor-bearing Schaffer collateral terminals, a transient 2-fold increase in Y-2, receptor affinity was observed after 4-12 hr, with a later slow decline. No change was seen in Y-2, mRNA expression in CA2/CA3 pyramidal cells, from which Schaffer collaterals originate. Conversely, in granule cells of the dentate gyrus, markedly elevated Y-2, mRNA concentrations were observed (by 740% in the dorsal hippocampus) 24-48 hr after kainate injection. At the same time, a marked and lasting (up to 6 months) increase in the number of Y-2, receptor sites (by 800%) was seen in the dentate hilus, which is innervated densely by mossy fibers. The early increase in Y-2, receptor affinity in Schaffer collaterals was accompanied by a 60% decrease in the EC50,, of peptide YY3-36,, in inhibiting K+-stimulated glutamate release in hippocampal slices from kainic acid-treated rats. Our data indicate transient up-regulation of presynaptic Y-2, receptors in Schaffer collaterals by a change in affinity and a permanent de novo synthesis of presynaptic Y-2, receptors in granule cells/mossy fibers. These changes may cause augmented presynaptic inhibition of glutamate release from different hippocampal sites and, in conjunction with increased concentrations of neuropeptide tyrosine in mossy fibers, may represent an endogenous reactive anticonvulsant mechanism.