The mechanisms of quisqualic acid induced sensitization of hippocampal slices to depolarization by L-2-amino-4-phosphonobutanoic acid (L-AP4)

Hippocampal CA1 pyramidal cell neurons are sensitized over 30 fold to depolarization by L-2-amino-4-phosphonobutanoic acid (L-AP4) following exposure to L-quisqualic acid (QUIS). This QUIS-induced increase in sensitivity has been termed the QUIS-effect. Sensitivity to AP4 and related phosphonates persists for several hours following exposure to L-QUIS. The QUIS-effect may represent an example of synaptic plasticity (the increase in efficiency of synaptic transmission) and thus may play an important role in learning and memory and in the excessive stimulation that characterizes seizure disorders and neurodegenerative diseases.; The mechanisms that underlie the QUIS-effect are unknown. Previous studies support the existence of at least two distinct receptor sites that play roles in the induction and expression of the QUIS-effect. The site or sites that interact with L-QUIS to induce sensitization of slices to L-AP4 are collectively referred to as the induction site. L-AP4 has no observed effect at this site. Several analogues of L-QUIS were tested for their ability to act at this induction site and produce sensitization to L-AP4.; It has been proposed that induction of the QUIS-effect may, in part, involve an uptake site for L-QUIS. This study utilizes o-phthaldialdehyde (OPA) derivatization and HPLC separation of extracts from hippocampal slices that have been exposed to varied concentrations of L-QUIS to investigate L-QUIS uptake into hippocampal slices. Rapid uptake of L-QUIS into slices was observed; reaching concentrative levels within 7 min. The properties of the uptake of L-QUIS suggest that it may be linked to the induction of the QUIS-effect.; The site that becomes sensitized by L-QUIS represents a second receptor site and has been termed the QUIS-sensitized AP4 site. To further characterize this site, 49 structural analogues of L-AP4, glutamic acid and L-QUIS were tested. The data show that the pharmacology of the QUIS-sensitized AP4 site is distinct from other known binding sites for L-AP4 in the CNS. Data obtained from the testing of L-QUIS analogues also suggest that, in addition to the well-known interaction of L-QUIS with the classical AMPA receptor, a novel QUIS site may exist in the hippocampal CA1 region.