Redox modulation of synaptic responses and plasticity in rat CA1 hippocampal neurons.
Effects of redox reagents on excitatory and inhibitory synaptic responses as well as on the bidrectional plasticity of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) 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 microM) did not affect AMPA, GABAA or GABAB receptor-mediated synaptic responses or the activation of presynaptic 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 presence of physiological concentrations of Mg2+ (1.3 mM), DTNB did not affect the NMDA receptor-dependent induction of long-term potentiation (LTP) or long-term depression (LTD) expressed by AMPA receptors. In contrast, DTNB fully prevented LTP and LTD induced and expressed by NMDA receptors. Plasticity of NMDA receptor-mediated synaptic responses could be reinstated by the reducing agent tris-(2-carboxyethyl) phosphine (TCEP, 200 microM). These results suggest that persistent, bidirectional changes in synaptic currents mediated by NMDA receptors cannot be evoked when these receptors are in an oxidized state, whereas NMDA-dependent LTP and LTD are still expressed by AMPA receptors. Our observations raise the possibility of developing therapeutic agents that would prevent persistent excitotoxic enhancement of NMDA receptor-mediated events without blocking longterm modifications of AMPA receptor-mediated synaptic responses, thought to underlie memory processes.
Bernard
C L
CL
INSERM U29, Hôpital de Port-Royal, Paris, France.
Hirsch
J C
JC
Khazipov
R
R
Ben-Ari
Y
Y
Gozlan
H
H
D000818:Animals; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology*; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects*
D004228:Dithionitrobenzoic Acid