The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus

The group I specific metabotropic glutamate (mGlu) receptor agonist ( RS)-3,5-dihydroxyphenylglycine (DHPG) (100 μM, 10 min) induced long-term depression (LTD) of synaptic transmission in the CA1 region of adult rat hippocampal slices, measured using a grease-gap recording technique. In “normal” (1 mM Mg 2+-containing) medium, LTD (measured 30 min after washout of DHPG) was small (13 ± 3%), but LTD was enhanced if DHPG was applied when the tissue was made hyperexcitable, either by omitting Mg 2+ from the perfusate (35 ± 3%) or by adding the GABA A receptor antagonist picrotoxin (29 ± 2%). The N-methyl- D-aspartate (NMDA) receptor antagonist AP5 (100 μM) substantially reduced the generation of DHPG-induced LTD in Mg 2+-free medium, but had little effect on LTD induced in the presence of picrotoxin. In Mg 2+-free medium, the threshold concentration of DHPG required to induce LTD was between 1 and 3 μM. Neither agonists specific for group II (100 nM DCG-IV or 1 μM LY354740) or group III (10 μM l-AP4) mGlu receptors or a combined group I and II agonist (30–100 μM (1 S,3 R)-ACPD) induced LTD. However, an agonist (1 mM CHPG) which activates mGlu 5 but not mGlu 1 receptors did induce LTD. Surprisingly, DHPG-induced LTD was reversed by mGlu receptor antagonists, applied hours after washout of DHPG. DHPG-induced LTD did not occlude with LTD induced by synaptic activation (1200 stimuli delivered at 2 Hz), in Mg 2+-free medium. These data show that activation of group I mGlu receptors (probably mGlu 5) can induce LTD and that this mGlu receptor-mediated LTD may, or may not, require activation of NMDA receptors, depending on the experimental conditions.