Group I metabotropic glutamate receptors enable two distinct forms of long-term depression in the rat dentate gyrus in vivo.

The existence of long-term depression (LTD) in the dentate gyrus of freely moving rats, as well as the contribution of different types of metabotropic glutamate receptors (mGluRs) to this form of plasticity, has been the subject of much debate. Here, we describe two distinct forms of mGluR-dependent hippocampal LTD in the dentate gyrus of freely moving adult rats. LTD, induced by low-frequency stimulation (LFS) of the medial perforant path (LFS-LTD), was prevented by antagonism of the phospholipase C-coupled receptors, mGluR1 but not mGluR5. Chemical LTD, induced by intracerebral application of the group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine, was blocked by antagonism of both mGluR5 and mGluR1. Selective activation of mGluR5, using (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), also led to chemical LTD. To test whether LFS-LTD and chemical LTD share common induction mechanisms, we applied LFS following the induction of chemical LTD by CHPG (CHPG-LTD). Surprisingly, LFS impaired CHPG-LTD. Further analysis revealed that induction of CHPG-LTD led to altered calcium dynamics sufficient for its reversal by LFS. We found that LTD induced by (R,S)-3,5-dihydroxyphenylglycine, but not by CHPG, is impaired by N-methyl-d-aspartate receptor antagonism. Both forms of chemical LTD strongly require calcium influx through L-type voltage-gated calcium channels. This contrasts with previous findings that LFS-LTD in the dentate gyrus is both N-methyl-d-aspartate receptor and voltage-gated calcium channel independent. LFS-LTD and LTD induced by group I mGluR agonists thus appear to comprise distinct forms of LTD that require the activation of specific group I mGluRs and recruit calcium from different sources.