Signal transduction pathways involved in the acute potentiation of NMDA responses by 1S,3R‐ACPD in rat hippocampal slices

Abstract

1 A grease-gap recording technique has been used to investigate the mechanisms underlying the acute potentiation of N-methyl-d-aspartate (NMDA) responses by aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) in area CA1 of rat hippocampal slices. 2 1S,3R-ACPD (10 μm), but not 1R,3S- ACPD (10 μm), potentiated submaximal responses to NMDA (dose-ratio of 0.81 ± 0.02 (mean ± s.e.mean); n = 55), but not to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), in a readily reversible manner. Potentiation also occurred in slices treated with 0.2 μm tetrodotoxin, and in slices perfused with Mg²⁺-free medium. 3 1S,3R-ACPD-induced potentiation was unaffected by the protein kinase inhibitors K-252b (0.1 μm) and staurosporine (1 μm) and the intracellular Ca²⁺ store depletor, thapsigargin (10 μm). Coapplication of staurosporine and thapsigargin was also without effect. 4 1S,3R-ACPD-induced potentiation was unaffected by inhibitors of arachidonic acid formation, bromophenacyl bromide (50 μm) and RG80267 (100 μm). Arachidonic acid (10–50 μm) depressed reversibly NMDA-induced responses. The potentiation was unaffected by 8-bromo cyclic AMP (500 μm) or the PKA inhibitor Rp-adenosine 3,5-cyclic monophosphothioate triethylamine (Rp-cAMPS; 50 μm). 5 1S,3R-ACPD-induced potentiation was abolished in slices perfused with Ca²⁺-free medium. The potentiation was also blocked by phorbol-12,13-diacetate (1 μm), in a staurosporine-sensitive manner. 6 It is concluded that the potentiation of NMDA responses by 1S,3R-ACPD is not mediated by protein kinase A or C., by release of Ca²⁺ from intracellular stores or by arachidonic acid. It involves a Ca²⁺-sensitive process and is negatively regulated by protein kinase C.