REDOX MODULATION OF SYNAPTIC RESPONSES AND PLASTICITY IN RAT CA1 HIPPOCAMPAL-NEURONS

Effects of redox reagents on excitatory and inhibitory synaptic respon ses as well as on the bidirectional plasticity of alpha-amino-3-hydrox y-5-methylisoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMD A) receptor-mediated synaptic responses were studied in CA1 pyramidal neurons in rat hippocampal slices. The oxidizing agent 5,5'-dithiobis( 2-nitrobenzoic acid) (DTNB, 200 mu M) did not affect AMPA, GABA(A) or GABA, receptor-mediated synaptic responses or the activation of presyn aptic metabotropic receptors. However, DTNB irreversibly decreased (by approximately 50%) currents evoked by focal application of NMDA. DTNB also decreased the NMDA component of the EPSC. The reversal potential of NMDA currents and the Mg2+ block were not modified. In the presenc e of physiological concentrations of Mg2+ (1.3 mM), DTNB did not affec t the NMDA receptor-dependent induction of long-term potentiation (LTP ) or long-term depression (LTD) expressed by AMPA receptors. In contra st, DTNB fully prevented LTP and LTD induced and expressed by NMDA rec eptors. Plasticity of NMDA receptor-mediated synaptic responses could be reinstated by the reducing agent tris-(2-carboxyethyl) phosphine (T CEP, 200 mu M). These results suggest that persistent, bidirectional c hanges in synaptic currents mediated by NMDA receptors cannot be evoke d when these receptors are in an oxidized state, whereas NMDA-dependen t LTP and LTD are still expressed by AMPA receptors. Our observations raise the possibility of developing therapeutic agents that would prev ent persistent excitotoxic enhancement of NMDA receptor-mediated event s without blocking longterm modifications of AMPA receptor-mediated sy naptic responses, thought to underlie memory processes.