INCREASED AMPA-SENSITIVE QUISQUALATE RECEPTOR-BINDING AND REDUCED NMDA RECEPTOR-BINDING IN EPILEPTIC HUMAN HIPPOCAMPUS

Based on results from the kindling model of epilepsy, we hypothesized that enhanced binding of radioligands to the NMDA receptor and decreased binding to the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive quisqualate (ASQ) receptor would be found within epileptic hippocampi of humans with complex partial epilepsy (CPE). To test these hypotheses, we used tissue that was surgically removed from patients with intractable CPE, and control tissue that was obtained at autopsy. We used autoradiographic techniques to measure ASQ receptor binding (with H-3-AMPA as the radioligand) and binding to 2 sites on the NMDA receptor/channel complex: the agonist recognition site (with H-3-glutamate) and the phencyclidine (PCP) binding site that resides within the NMDA channel [with H-3-N-{1-[thienyl]cyclohexyl}piperidine (TCP) in the presence of saturating concentrations of NMDA and glycine]. Measurements of receptor binding were corrected for pathologic alterations in neuronal density. Contrary to our expectations, ASQ receptor binding was significantly increased (100%; p < 0.02) in the dentate gyrus stratum moleculare in patients with CPE (n = 8), and it was unchanged in other hippocampal regions. In nearby sections from the same specimens, binding was significantly decreased to the agonist recognition site of the NMDA receptor in the stratum oriens of area CA3 (46%; p < 0.05) and was also decreased to the PCP site in the stratum radiatum and stratum oriens of CA3 (44% and 74%, respectively; p < 0.05). The increase in ASQ receptor binding may contribute to hyperexcitability in these epileptic patients. The decreased NMDA receptor binding may reflect an injured neuronal population, a selective loss of the most NMDA-sensitive neurons, or a homeostatic down-regulation of hyperexcitability by surviving neurons. Kindling does not appear to model CPE that is associated with mesial temporal sclerosis.