IN CA1 HIPPOCAMPAL-NEURONS, THE REDOX STATE OF NMDA RECEPTORS DETERMINES LTP EXPRESSED BY NMDA BUT NOT BY AMPA RECEPTORS

1. Using extracellular recording techniques in the CA1 region of the r at hippocampus, we have evaluated the effects of the redox reagents 5, 5O-dithiobis-2-nitrobenzoic acid (DTNB) and tris(carboxyethyl) phosphi ne (TCEP) on long-term potentiation (LTP) expressed by pha-amino-3-hyd roxy-5-methyl-isoxazole-4-propionic acid (AMPA) and N-methyl-D-asparta te (NMDA.) receptors. In physiological conditions st high-frequency st imulation (HFS) of Schaffer collateral-commissural fibers induced a LT P expressed by a persistent increase (73 +/- 13%, mean +/- SE, n = 8/1 0) of AMPA. field potentials (LTP(A)). In the presence of 10 mu M of 6 -cyano-7-nitroquinoxaline-2,3-dione (CNQX) and reduced concentration o f Mg2+ (0.1 mM) to boost NMDA receptors, the HFS induced LTP of NMDA f ield potentials (LTP(N); 62 +/- 11%, n = 8/10). 2. The thiol-oxidizing reagent DTNB (200 mu M) reduced, by 46 +/- 5% (n = 24), NMDA-receptor field potentials (NMDA-FP), and this effect could not be reversed by extensive washing. The disulfide-reducing agent TCEP (200 mu M) slight ly increased AMPA-FP and reversed the DTNB-induced inhibition of NMDA- FP. 3. DTNB (200 mu M, 10 min), and TCEP (200 mu M, 20 min), had no ef fect on AMPA-FP (98 +/- 3% and 101 +/- 5%, respectively, n = 12). 4. D TNB (200 mu M, 15 min) did not prevent the induction or expression of LTP(A) (-12 and -5%, respectively, n = 8/8). Similar results were obse rved with TCEP (200 mu M, 20 min). 5. In contrast, DTNB (200 mu M) pre vented the induction of LTP(N) (14 +/- 6%, n = 8).This effect was reve rsed by the disulfide-reducing reagent TCEP (200 mu M) but not by exte nsive washing. The expression of LTP(N) was reduced by DTNB (-52 +/- 6 %, n = 8/8) and restored by TCEP (200 mu M; 56 +/- 13%, n = 4/4). 6. T he blockade of the induction of LTP(N) by DTNB was not due to a reduct ion of the NMDA-mediated responses because 1) increasing the intensity of stimulation under oxidizing conditions before HFS did not restore the induction of LTP(N) and 2) a similar irreversible blockade by MK 8 01 (-56 +/- 4%) did not prevent LTP(N) (49 +/- 9%, n = 8/12). 7. These observations have two important implications. 1) The induction of LTP (A) that requires NMDA receptor activation does not depend on the redo x state of the latter receptor. 2) The induction and the expression of LTP(N) that also requires NMDA receptor activation is controlled by t he redox state of these receptors.