EVIDENCE FOR INVOLVEMENT OF THE CGMP PROTEIN-KINASE-G SIGNALING SYSTEM IN THE INDUCTION OF LONG-TERM DEPRESSION, BUT NOT LONG-TERM POTENTIATION, IN THE DENTATE GYRUS IN-VITRO

The involvement of the cGMP-protein kinase G (PKG) signaling pathway i n the induction of long-term depression (LTD) and long-term potentiati on (LTP) was investigated in the medial perforant path of the dentate gyrus in vitro. Low-frequency stimulation (LFS)-induced LTD of field E PSPs was inhibited by bath perfusion of the selective soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) . LFS-induced LTD of EPSPs and whole-cell patch-clamped EPSCs was also blocked by bath perfusion and postsynaptic intracellular injection, r espectively, of the selective PKG inhibitor KT5823. Elevation of intra cellular cGMP by perfusion of the cGMP phosphodiesterase inhibitor zap rinast resulted in induction of LTD of field EPSPs and EPSCs. Occlusio n experiments showed mutual inhibition between LFS-induced LTD and zap rinast-induced LTD. The zaprinast-induced LTD of field EPSPs was inhib ited by perfusion of ODQ and KT5823. In addition, zaprinast-induced LT D of EPSCs was inhibited by postsynaptic application of KT5823. Glutam ate receptor stimulation, especially that of metabotropic glutamate re ceptors (mGluRs), was required for zaprinast-induced LTD, because cess ation of test stimulation or perfusion with the mGluR antagonist (+)-a lpha-methyl-4-carboxyphenylglycine (MCPG) inhibited zaprinast-induced LTD. No inhibitory effect of ODQ or KT5823 on the induction of LTP of EPSPs or EPSCs was found. These data indicate that the cGMP-guanyly cy clase-PKG signaling pathway in the dentate gyrus is essential for indu ction of LTD, although not of LTP, in the dentate gyrus.