NMDA-Independent Long-Term Depression of Synaptic Transmission in the Hippocampus: Mechanisms of Induction and Effects of Nootropic Drugs

Abstract

In studies on transversal slices of the rat dorsal hippocampus, we found that low-frequency tetanic stimulation of the medial perforant pathway (2 sec-1, 7.5 min) results in long-term depression (LTD) of field EPSP of granular cells in the dentate gyrus. This synaptic plasticity phenomenon was weakened by calmodulin, nitric oxide synthase, and protein kinase C inhibitors, trifluoperazine (1 μM), N-nitro-L-arginine (5 μM), and polymixin B (50 μM), respectively, but was enhanced by a nonselective inhibitor of cAMP phosphodiesterases, 1-isobuthyl-3-methylxanthine (100 μM), and a calcineurin inhibitor, cyclosporin A (50 μM). The nootropic activity-possessing drugs piracetam, carbacetam, and etimizole suppressed, in a dose-dependent manner, the induction and expression of the studied form of LTD of synaptic transmission, but glycine did not. We assume that Ca2+- and protein kinase G-mediated increase in the activity of calmodulin is the main link in the induction of this LTD form. Calmodulin, via NO synthase and adenylate cyclase, increases the activities of protein kinase C, a substrate of the latter, and inhibitor 1. Under the influence of piracetam, carbacetam, and etimizole, the calmodulin concentration in the cytoplasm of dendritic spines attains a level sufficient for activation of Ca2+/calmodulin-dependent protein kinase, which provides for the phosphorylation of AMPA receptors and interferes with the development of LTD of synaptic transmission.