Modulation of AMPA receptor kinetics differentially influences synaptic plasticity in the hippocampus.

Prior studies showed that positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators facilitate long-term potentiation (LTP) and improve the formation of several types of memory in animals and humans. However, these modulators are highly diverse in their effects on receptor kinetics and synaptic transmission and thus may differ also in their efficacy to promote changes in synaptic strength. The present study examined three of these modulators for their effects on synaptic plasticity in field CA1 of hippocampal slices, two of them being the benzamide drugs 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) which prominently enhance synaptic transmission yet differ in their relative impact on amplitude versus duration of the synaptic response. The third drug was cyclothiazide which potently blocks AMPA receptor desensitization. Effects on plasticity were assessed by measuring (i) the likelihood of obtaining stable potentiation when using theta-burst stimulation with three instead of four pulses per burst, (ii) the maximum amount of potentiation under optimal stimulation conditions, and (iii) the effect on long-term depression (LTD). Both benzamides facilitated the formation of stable potentiation induced with three-pulse burst stimulation which is normally ineffective. CX546 in addition increased maximally inducible potentiation after four-pulse burst stimulation from about 50% to 100%. Burst response analysis revealed that CX546 greatly prolonged the duration of depolarization by slowing the decay of the response which thus presumably leads to a more continuous N-methyl-D-aspartate (NMDA) receptor activation. Cyclothiazide was ineffective in increasing maximal potentiation in either field or whole-cell recordings. CX546, but not CX516, also enhanced nearly two-fold the NMDA receptor-dependent long-term depression induced by heterosynaptic 2 Hz stimulation. Tests with recombinant NMDA receptors (NR1/NR2A) showed that CX516 and CX546 have no direct effects on currents mediated by these receptors. These results suggest that (1) modulation of AMPA receptors which increases either response amplitude or duration can facilitate LTP formation, (2) modulators that effectively slow response deactivation augment the maximum magnitude of LTP and LTD, and (3) receptor desensitization may have a minor impact on synaptic plasticity in the hippocampus. Taken together, our data indicate that AMPA receptor modulators differ substantially in their ability to enhance synaptic potentiation or depression, depending on their particular influence on receptor kinetics, and hence that they may also be differentially effective in influencing higher-order processes such as memory encoding.