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

Neuropharmacology. 1999 Jan;38(1):73-83. doi: 10.1016/s0028-3908(98)00168-3.


The involvement of metabotropic glutamate receptor group II (mGluRII) in the induction of long-term depression (LTD) was investigated in the medial perforant 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 agonist, by LTD. The reversible inhibition was associated with a change in paired 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 reduction in the number of active release sites, or a postsynaptic change. Further evidence that the DCG-IV-induced LTD was generated by activation of mGluRII was the finding that the mGluRII antagonist (RS)-alpha-methylserine-O-phosphate 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 part, 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-phosphonopentanoate (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 inhibitor H-89. The study demonstrates that activation of mGluRII induces LTD via activation the PKA and PKC pathways in the medial perforant path of the dentate gyrus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP-Dependent Protein Kinases / drug effects*
  • Dentate Gyrus / drug effects*
  • Dentate Gyrus / enzymology
  • Enzyme Activation
  • Excitatory Postsynaptic Potentials / drug effects
  • In Vitro Techniques
  • Neuronal Plasticity / drug effects*
  • Presynaptic Terminals / drug effects
  • Protein Kinase C / drug effects*
  • Rats
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, N-Methyl-D-Aspartate / drug effects


  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C