Expression of LTP by AMPA and/or NMDA receptors is determined by the extent of NMDA receptors activation during the tetanus

Abstract

1. We have tested, in CA1 hippocampal slices, the hypothesis that the expression of long-term potentiation (LTP) by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and/or N-methyl-D-aspartate (NMDA) receptors depends on the degree of NMDA receptors activation during the tetanus. 2. Slices were perfused in an artificial cerebrospinal fluid (ACSF) containing glycine (1 microM), bicuculline (5 microM) and a low Mg2+ concentration (0.3 mM). To measure the AMPA and NMDA receptor-mediated field excitatory postsynaptic potential (fEPSPA and fEPSPN, respectively), we have used the following procedure: control fEPSPA was first measured, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) was then added, and fEPSPN was evoked. CNQX was washed, and once control fEPSPA was recorded, the Schaffer collaterals were tetanized at a weak or a strong intensity. The slope of fEPSPA was measured for 30-45 min followed by that of fEPSPN after the application of CNQX. 3. At a weak intensity (TW, which corresponds to a fEPSPA of approximately 0.3 mV of amplitude and no fEPSPN), the tetanic stimulation generated LTP of fEPSPA (58.7 +/- 8.1% mean +/- SE, n = 9) but no significant potentiation of the fEPSPN (11.2 +/- 2.2%, n = 9). These values were significantly different (P < 0.05, analysis of variance, Fisher test). 4. In 9 of 13 slices, tetanic stimulation of strong intensity (Ts, intensity corresponding to a fEPSPN of approximately 0.3 mV of amplitude) generated LTP of fEPSPN (89.1 +/- 17.2%) but not of fEPSPA (9.44 +/- 2.8%). In the four remaining slices the tetani induce LTP of both fEPSPA and fEPSPN (81.7 +/- 14.7% and 101 +/- 35.6%, respectively, both values were not significantly different). 5. We then examined the effects of decreasing fEPSPN by 50% in LTP generated by Ts and Tw. In the presence of 7-Chlorokynurenate (7Cl(-)-Kyn; 6 microM; n = 6), an antagonist of the allosteric glycine site of the NMDA receptors, Ts generated LTP of fEPSPA (63.2 +/- 8.2%) but not of fEPSPN (12.6 +/- 4.0%). Both values were significantly different. Tw still evoked LTP of fEPSPA but of smaller magnitude (29.8 +/- 6.3%, n = 8) than the one obtained in the absence of the antagonist (58.7 +/- 8.1%). Both values were significantly different. 6. The present observation suggests that l) LTP of fEPSPA has a lower threshold than that of fEPSPN, i.e., stronger activation of NMDA receptors during the tetani is required to induce LTP of fEPSPN than the one required for inducing LTP of fEPSPA; and 2) there is a bell-shaped relationship between the degree of activation of NMDA receptors during the tetani and the magnitude of LTP of the fEPSPA: tetani that generate LTP of fEPSPN have a low probability to induce LTP of fEPSPA. We suggest that AMPA and NMDA components are potentiated through two different presumably postsynaptic processes.