Elsevier

Neuropharmacology

Volume 54, Issue 5, April 2008, Pages 804-814
Neuropharmacology

Group III mGluR regulation of synaptic transmission at the SC-CA1 synapse is developmentally regulated

https://doi.org/10.1016/j.neuropharm.2007.12.009Get rights and content

Abstract

Group III metabotropic glutamate receptors (mGluRs) reduce synaptic transmission at the Schaffer collateral-CA1 (SC-CA1) synapse in rats by a presynaptic mechanism. Previous studies show that low concentrations of the group III-selective agonist, L-AP4, reduce synaptic transmission in slices from neonatal but not adult rats, whereas high micromolar concentrations reduce transmission in both age groups. L-AP4 activates mGluRs 4 and 8 at much lower concentrations than those required to activate mGluR7, suggesting that the group III mGluR subtype modulating transmission is a high affinity receptor in neonates and a low affinity receptor in adults. The previous lack of subtype selective ligands has made it difficult to test this hypothesis. We have measured fEPSPs in the presence of novel subtype selective agents to address this question. We show that the effects of L-AP4 can be blocked by LY341495 in both neonates and adults, verifying that these effects are mediated by mGluRs. In addition, the selective mGluR8 agonist, DCPG, has a significant effect in slices from neonatal rats but does not reduce synaptic transmission in adult slices. The mGluR4 selective allosteric potentiator, PHCCC, is unable to potentiate the L-AP4-induced effects at either age. Taken together, our data suggest that group III mGluRs regulate transmission at the SC-CA1 synapse throughout development but there is a developmental regulation of the subtypes involved so that both mGluR7 and mGluR8 serve this role in neonates whereas mGluR7 is involved in regulating transmission at this synapse throughout postnatal development.

Introduction

Glutamate is the major excitatory neurotransmitter in the brain and can exert its effects through activation of both ionotropic and metabotropic glutamate receptors (mGluRs). The mGluRs are members of the family C G protein-coupled receptors (GPCRs). Eight mGluR subtypes have been identified from mammalian brain and are grouped into three groups based on their sequence homologies, ligand selectivity, and downstream effector molecules. Group I mGluRs include mGluR1 and mGluR5 which couple to Gq and activate PLCβ. mGluRs 2 and 3 comprise Group II and mGluRs 4, 6, 7, and 8 comprise Group III. The members of Groups II and III couple to Gi/o which results in modulation of multiple effector systems, including various ion channels and inhibition of adenylyl cyclase (see Conn and Pin, 1997 for review).

One of the most common physiological effects of mGluR activation that is consistent throughout the central nervous system is a role as presynaptic autoreceptors involved in reducing transmission at glutamatergic synapses. For instance, activation of mGluRs reduces transmission at each of the major glutamatergic synapses in the hippocampal formation. Interestingly, evidence suggests that different mGluR subtypes serve this role in each major hippocampal synapse (Gereau and Conn, 1995b, Kamiya and Ozawa, 1999, Koerner and Cotman, 1981, Koerner and Cotman, 1982, Lanthorn et al., 1984, Macek et al., 1996). One of the most important synapses in the hippocampal circuit that is often implicated in learning and memory is the synapse between CA3 pyramidal cell axons, termed Schaffer collaterals (SC), and CA1 pyramidal cells (SC-CA1 synapse). Previous studies suggest that Group III mGluRs attenuate transmission at the SC-CA1 synapse by a presynaptic mechanism (Baskys and Malenka, 1991, Gereau and Conn, 1995a, Gereau and Conn, 1995b, Vignes et al., 1995). Baskys and Malenka (1991) found that 50 μM L-AP4, a selective agonist of group III mGluRs, attenuates transmission at this synapse in slices from neonatal but not adult rats. These data suggested that group III mGluRs may only participate in regulation of transmission at the SC-CA1 synapse at early stages of postnatal development. However, subsequent studies revealed that higher concentrations of L-AP4 (500 μM) have similar effects on transmission at this synapse in slices from neonatal and adult animals (Gereau and Conn, 1995a), suggesting that group III mGluRs regulate SC-CA1 transmission throughout postnatal development. A difference in the effect of 50 μM versus 500 μM L-AP4 raises the possibility of a developmental regulation of the specific group III mGluR subtype(s) that serve this role in neonatal versus adult animals. For instance, L-AP4 has nanomolar potencies at mGluR4 and mGluR8 but micromolar potency at mGluR7 (Schoepp et al., 1999). Thus, mGluR4 or 8 could predominate at early postnatal stages while mGluR7 could serve as the predominant receptor mediating this response in adults. However, the reduction in sensitivity to L-AP4 could also be due to the presence of high receptor reserve in neonatal animals and a developmental decrease in expression of a single group III mGluR subtype, leading to loss of receptor reserve and reduced agonist potency. In support of the possibility that mGluR7 is the only group III mGluR subtype involved in regulating transmission at this synapse in adults, immunohistochemical analysis of Group III mGluRs in the adult rat hippocampus revealed that mGluR4a is primarily localized to the inner third of the molecular layer and mGluR8 is found in the lateral perforant path terminal zone. In contrast, mGluR7a is distributed in all dendritic layers throughout the hippocampus (Bradley et al., 1996, Corti et al., 2002, Kosinski et al., 1999, Shigemoto et al., 1997). While immunohistochemical analysis has not been performed for all group III mGluR subtypes in neonates, antibodies to mGluR7a in the neonatal (p7) rat hippocampus revealed that this receptor is not highly expressed in the stratum radiatum of the CA1 region (Bradley et al., 1998). Thus, it is unlikely that mGluR7 expression and receptor reserve are higher in neonates than adults. Therefore, it is possible that another mGluR subtype is expressed in neonates and is responsible for the higher potency of L-AP4.

Unfortunately, pharmacological reagents that clearly differentiate between the group III mGluR subtypes have not been available, making it impossible to directly determine the mechanism for this difference. However, recent efforts have provided novel pharmacological tools that provide greater selectivity between group III mGluR subtypes (Marino et al., 2003a, Marino et al., 2003b, Mitsukawa et al., 2005, Thomas et al., 2001, Zhai et al., 2002) than previously available compounds. We have used these newer reagents to rigorously test the hypothesis that there is a developmental regulation of the presynaptic mGluR subtypes involved in regulating transmission at this synapse and to determine which mGluR subtypes mediate this effect at the different stages of postnatal development.

Section snippets

Compounds

l-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) and N,N′-dibenzhydrylethane-1,2-diamine (AMN082) were purchased from Ascent Scientific (Weston-Super-Mare, UK) or Tocris Bioscience (Ellisville, MO). (S)-3,4-Dicarboxyphenylglycine ((S)-DCPG), N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), and 2S-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-xanth-9-yl) propanoic acid (LY341495), were purchased from Tocris Bioscience (Ellisville, MO). Z-Cyclopentyl AP4 ((Z)-1(RS)-amino-3(RS

L-AP4 has higher potency at reducing synaptic transmission at the SC-CA1 synapse in neonatal rats than in adults

As a first step to testing the hypothesis that a group III mGluR with relatively high affinity for L-AP4 (mGluR4 or mGluR8) regulates transmission at the SC-CA1 synapse in neonates, we determined the effects of multiple concentrations of L-AP4 on evoked fEPSPs at this synapse in slices from neonatal animals. Consistent with a previous study (Baskys and Malenka, 1991), 50 μM L-AP4 induced a significant reduction of fEPSP slope (65 ± 8.7% of predrug; P < 0.01) (Fig. 1A). A concentration response curve

Discussion

The present data suggest that there is a dramatic developmental regulation of presynaptic receptors involved in regulating transmission at the SC-CA1 synapse. Interestingly, while group III mGluRs provide robust modulation of transmission at this synapse throughout development, there is a developmental switch in the specific subtypes responsible for this effect. Specifically, our data suggest that mGluR7 and mGluR8 are the most likely candidates for receptors involved in regulating synaptic

Acknowledgments

The authors thank Dr. Rodney Johnson (University of Minnesota, Minneapolis, MN) for the Z-cyclopentyl AP4, Dr. Huai Hu Chang and Dr. Lily Jan (University of San Francisco, San Francisco, CA) for stable HEK/GIRK cells, and K. Johnson and C. Kim for stable transfection of HEK/GIRK cells with mGluR constructs. This work was supported by grants from National Institute of Mental Health and National Institute of Neurological Disorders and Stroke. Vanderbilt is a site in the National Institutes of

References (43)

  • M. Vignes et al.

    Pharmacological evidence for an involvement of group II and group III mGluRs in the presynaptic regulation of excitatory synaptic responses in the CA1 region of rat hippocampal slices

    Neuropharmacology

    (1995)
  • M. Yoshino et al.

    A metabotropic glutamate receptor agonist DCG-IV suppresses synaptic transmission at mossy fiber pathway of the guinea pig hippocampus

    Neurosci. Lett.

    (1996)
  • J. Zhai et al.

    Modulation of lateral perforant path excitatory responses by metabotropic glutamate 8 (mGlu8) receptors

    Neuropharmacology

    (2002)
  • A. Baskys et al.

    Agonists at metabotropic H glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus

    J. Physiol.

    (1991)
  • S.R. Bradley et al.

    Immunocytochemical localization of group III metabotropic glutamate receptors in the hippocampus with subtype-specific antibodies

    J. Neurosci.

    (1996)
  • S.R. Bradley et al.

    Distribution and developmental regulation of metabotropic glutamate receptor 7a in rat brain

    J Neurochem.

    (1998)
  • A.M. Canudas et al.

    PHCCC, a specific enhancer of type 4 metabotropic glutamate receptors, reduces proliferation and promotes differentiation of cerebellar granule cell neuroprecursors

    J. Neurosci.

    (2004)
  • P.J. Conn et al.

    mGluR7's lucky number

    Proc. Natl. Acad. Sci. USA

    (2006)
  • P.J. Conn et al.

    Pharmacology and functions of metabotropic glutamate receptors

    Annu. Rev. Pharmacol. Toxicol.

    (1997)
  • S.L. Crooks et al.

    Cyclic analogues of 2-amino-4-phosphonobutanoic acid (APB) and their inhibition of hippocampal excitatory transmission and displacement of [3H]APB binding

    J. Med. Chem.

    (1986)
  • T.V. Dunwiddie

    Age-related differences in the in vitro rat hippocampus. Development of inhibition and the effects of hypoxia

    Dev. Neurosci.

    (1981)
  • Cited by (0)

    1

    Present address: College of Medicine Office of Research, University of South Florida, Tampa, FL 33612, USA.

    View full text