Differential expression of short-term potentiation by AMPA and NMDA receptors in dentate gyrus.

Abstract

Both alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) glutamatergic receptor subtypes in hippocampus have been shown to express long-term potentiation (LTP), a form of synaptic modification believed to be involved in memory formation. Because of their postsynaptic localization, any differential expression of LTP by the two receptor subtypes would strongly support the existence of a postsynaptic mechanism of LTP expression. In this study, electrophysiological recordings from dentate granule cells were used to compare the potentiation of AMPA and NMDA receptor-mediated responses occurring during the initial phase of LTP, typically identified as STP. Results revealed that high-frequency stimulation (HFS) of perforant path afferents induces a robust STP of both AMPA and NMDA receptor-mediated components of granule cell EPSPs (referred to as AMPA STP and NMDA STP, respectively). Although STP for both receptor subtypes decayed to an asymptotic, steady-state level of LTP and could be induced repetitively, there were substantial differences in several aspects of AMPA and NMDA STP dynamics. STP of the AMPA receptor reached its peak magnitude approximately 30 sec after HFS and decayed with a time constant of approximately 6 min. In contrast, peak magnitude of NMDA STP always appeared immediately after HFS and decayed with a time constant of only 1 min. Single-pulse stimulation of perforant path afferents paired with postsynaptic depolarization also induced LTP of both AMPA and NMDA components. When this induction paradigm was used, however, only the AMPA component showed significant STP. Our results demonstrate that AMPA and NMDA receptors exhibit markedly different degrees of activity-dependent, short-term modifiability, with the possibility that STP of the NMDA receptor reflects primarily post-tetanic potentiation (PTP). In addition, our results strongly suggest that the mechanisms underlying STP of the AMPA receptor are postsynaptic in origin.