Activation of mGluRII induces LTD via activation of protein kinase A and protein kinase C in the dentate gyrus of the hippocampus in vitro

The involvement of metabotropic glutamate receptor group II (mGluRII) in th e induction of long-term depression (LTD) was investigated in the medial pe rforant path of the rat dentate gyrus, a region with a very high density of mGluRII. Perfusion of either of two potent mGluRII agonists, (2S, 1R, 2R, 3R)-2-(2S, 1'R, 2'R, 3'R)-2 (2' 3'-dicarboxycyclopropyl)glycine (DCG-IV) or (+)-2-aminobicyclo[3.1.0]hexane-2-6-dicarboxylic acid (LY354740) induced a reversible inhibition of the field EPSP followed, upon washout of the agon ist, by LTD. The reversible inhibition was associated with a change in pair ed pulse depression, indicating an underlying presynaptic reduction in the probability of transmitter release, whereas the LTD was not associated with a change in paired pulse depression, indicating either a presynaptic reduc tion in the number of active release sites, or a postsynaptic change. Furth er evidence that the DCG-IV-induced LTD was generated by activation of mGlu RII was the finding that the mGluRII antagonist (RS)-alpha-methylserine-O-p hosphate monophenylphosphoryl ester (MSOPPE) prevented the induction of the LTD induced by DCG-IV. The DCG-IV-induced LTD showed mutual occlusion with LFS-induced LTD. The generation of the agonist-induced LTD required: in pa rt, activation of N-methyl-D-aspartate receptors (NMDAR), as LTD induction was partially blocked in the presence of the NMDAR antagonist D-2-amino-5-p hosphonopentanoate (AP5). Evidence for involvement of protein kinase C (PKC ) and protein kinase (PKA) in the induction of LTD by activation of mGluRII was obtained by showing an inhibition of the DCG-IV-induced LTD by the PKC inhibitors Ro-31-8220 and bisindolylmaleimide I, and also by the PKA inhib itor H-89. The study demonstrates that activation of mGluRII induces LTD vi a activation the PKA and PKC pathways in the medial perforant path of the d entate gyrus. (C) 1999 Elsevier Science Ltd. All rights reserved.