Differential involvement of group II and group III mGluRs as autoreceptors at lateral and medial perforant path synapses

Abstract

1. Previous reports have shown that group III metabotropic glutamate receptors (mGluRs) serve as autoreceptors at the lateral perforant path, but to date there has been no rigorous determination of the roles of other mGluRs as autoreceptors at this synapse. Furthermore, it is not known which of the mGluR subtypes serve as autoreceptors at the medial perforant path synapse. With the use of whole cell patch-clamp and field excitatory postsynaptic potential (fEPSP) recording techniques, we examined the groups of mGluRs that act as autoreceptors at lateral and medial perforant path synapses in adult rat hippocampal slices. 2. Consistent with previous reports, the group III mGluR agonist (D,L)-2-amino-4-phosphonobutyric acid reduced fEPSPs and excitatory postsynaptic currents (EPSCs) in the dentate gyrus. However, the group-II-selective agonist (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) also reduced fEPSPs and EPSCs, suggesting that multiple mGluR subtypes may serve as autoreceptors at perforant path synapses. 3. Selective activation of either medial or lateral perforant pathways revealed that micromolar concentrations of (L)-2-amino-4-phosphonobutyric acid (L-AP4) reduce fEPSPs in lateral but not medial perforant path, suggesting group III involvement at the lateral perforant pathway. Conversely, DCG-IV and 2R, 4R-4-aminopyrrolidine-2,4-dicarboxylate, another group-II-selective mGluR agonist, potently reduced fEPSPs at the medial but not lateral perforant path, suggesting that a group II mGluR may act as an autoreceptor at the medial perforant path-dentate gyrus synapse. 4. Antagonist studies with group-selective antagonists such as (2S,3S,4S)-2-methyl-2-(carboxycyclpropyl)glycine (MCCG; group II) and alpha-methyl-L-AP4 (MAP4; group III) suggest differential involvement of each group at these synapses. The effect of L-AP4 at the lateral perforant path synapse was blocked by MAP-4, but not MCCG. In contrast, the effect of DCG-IV was blocked by application of MCCG, but not MAP4. 5. Previous studies suggest that the effect of L-AP4 at the lateral perforant path synapse is mediated by a presynaptic mechanism. In the present studies, we found that concentrations of DCG-IV that reduce transmission at the medial perforant path synapse reduce paired-pulse depression and do not reduce kainate-evoked currents recorded from dentate granule cells. This is consistent with the hypothesis that DCG-IV also acts by a presynaptic mechanism.

Input-specific plasticity at excitatory synapses mediated by endocannabinoids in the dentate gyrus

“…MPP, but not MCF, are sensitive to inhibition by group II metabotropic glutamate receptor (mGluR) agonists. Consistent with a previous report (Macek et al, 1996), we found that 1 μM DCG-IV strongly reduced MPP-EPSC by 74.7 ± 1.2 % at 10-15 minutes post drug application (n = 3, p<0.01; Figure 1B). In contrast, DCG-IV at this concentration had no effect on MCF-EPSC (102.9 ± 6.2 % of baseline, p>0.05).…”

Group II metabotropic glutamate receptors inhibit glutamate release at thalamocortical synapses in the developing somatosensory cortex

“…Our results extend these earlier observations by showing that presynaptic mGluRs inhibit thalamocortical synapses and that group II mGluRs mediate the inhibition in developing mice. Previous reports indicate that mGluRs can be either maintained into adulthood (Macek et al, 1996, Yokoi et al, 1996, Flavin et al, 2000 or lost during development (Baskys and Malenka, 1991, Ross et al, 2000, Doherty et al, 2004. Therefore, it is also possible that the group II mGluRmediated modulation of thalamocortical EPSCs is important only during development and does not occur in the adult brain despite the expression of group II mGluRs in the barrels of adult rats and mice (Ohishi et al, 1998, Muñoz et al, 1999.…”

Differential Synaptic Integration of Interneurons in the Outer and Inner Molecular Layers of the Developing Dentate Gyrus

“…Immunocytochemical and physiological analyses have previously shown that glutamatergic transmission from MPP and LPP onto excitatory dentate granule cells, which have dendritic fields spanning the entire ML, are specifically inhibited by group II and III presynaptic metabotropic glutamate receptors (mGlus), respectively (Macek et al, 1996). Because OML interneurons only possess dendrites in the OML, not in the MML, and the opposite is true for IML interneurons (Fig.…”