Group II mGluR-induced long term depression in the dentate gyrus in vivo is NMDA receptor-independent and does not require protein synthesis

https://doi.org/10.1016/j.neuropharm.2005.06.018Get rights and content

Abstract

Long term depression (LTD) can be induced by low frequency stimulation (LFS) as well as by agonist activation of neurotransmitter receptors. Group II metabotropic glutamate receptors (mGluRs) play an essential role in the regulation of electrically-induced LTD in the hippocampus in vivo: LTD is inhibited by antagonists, and enhanced by agonists of group II mGluRs. Here we investigated induction of LTD by activation of group II mGluRs as well as the cellular mechanisms which might mediate group II mGluR-induced LTD. Rats were implanted with electrodes to enable chronic measurement of evoked potentials from medial perforant path–dentate gyrus synapses. Drug application was made through a cannula implanted into the ipsilateral cerebral ventricle. LTD could be induced by agonist activation of either group II mGluRs, or the group II mGluR subtype, mGluR3. Both, group II mGluR-induced LTD and mGluR3-induced LTD were not abolished by mRNA/protein synthesis inhibition. Furthermore, mGluR3-induced LTD was not inhibited by NMDA receptor antagonists or altered by L-type voltage-gated calcium channel blockers. Our data suggest that sole activation of group II mGluRs can mediate LTD in vivo. Intriguingly, this form of LTD is not dependent on protein synthesis or activation of NMDA receptors.

Introduction

Synaptic plasticity represents a use-dependent change in synaptic strength. A long-lasting weakening of synaptic efficacy, in the form of long term depression (LTD), is usually evoked by low frequency stimulation (LFS; Barrionuevo et al., 1980, Dudek and Bear, 1992) but can also be induced by pharmacological manipulations. These include agonist activation of receptors (Manahan-Vaughan and Reymann, 1995a, Manahan-Vaughan and Reymann, 1995b, Palmer et al., 1997, Lee et al., 1998) or activation/inactivation of intracellular messengers (Santschi et al., 1999, Bailey et al., 2003).

The mGluRs are subdivided into three main groups based on their signalling mechanisms and agonist preferences (Conn and Pin, 1997). Whereas group I mGluRs are positively coupled to phospholipase C (Abe et al., 1992, Aramori and Nakanishi, 1992) groups II and III mGluRs are negatively coupled to adenylyl cyclase (Nakajima et al., 1993, Okamoto et al., 1994, Tanabe et al., 1992, Tanabe et al., 1993). However, activation of group II mGluRs has also been reported to potentiate increases in cAMP accumulation triggered by activation of receptors which are positively coupled to adenylyl cyclase (Winder and Conn, 1995).

It has been extensively described that sole activation of any of the three mGluR subgroups can lead to LTD (Manahan-Vaughan and Reymann, 1995a, Manahan-Vaughan and Reymann, 1995b, Manahan-Vaughan and Reymann, 1997, Palmer et al., 1997, Huang et al., 1999a; Naie and Manahan-Vaughan, 2003). For example, group I mGluR activation induces a long-lasting depression in hippocampal slices (Palmer et al., 1997, Camodeca et al., 1999) which is protein synthesis-dependent (Huber et al., 2000). Naie and Manahan-Vaughan (2003) subsequently verified the existence of this in vivo. Robust synaptic depression is also induced by agonist activation of group II mGluRs (Manahan-Vaughan and Reymann, 1995b, Manahan-Vaughan and Reymann, 1997) and group III mGluRs (Manahan-Vaughan and Reymann, 1995a) in vivo. Investigations into the induction mechanisms of mGluR-induced LTD indicate that group I mGluR-induced LTD represents a novel form of LTD (Palmer et al., 1997, Schnabel et al., 1999) whereas group II mGluR-induced LTD shares common intracellular mechanisms with LFS-induced LTD (Huang et al., 1999a, Huang et al., 1999b). While group III mGluR-mediated LTD is not protein synthesis-dependent (Naie and Manahan-Vaughan, 2005), it is not yet known if group II mGluR-mediated LTD relies on protein synthesis.

Inactivation of PKA coupled with activation of cGMP leads to induction of chemical LTD in the hippocampus (Santschi et al., 1999). Weak patterned electrical stimulation combined with PKA inhibition also generates LTD (Stricker and Manahan-Vaughan, unpublished observations). Thus a link may exist between the induction of LTD by activation of mGluRs and the regulation of PKA. Here, the mGluRs that are negatively coupled to adenylyl cyclase (AC) comprise interesting candidates, as activation of AC-coupled mGluRs lead to inhibition of AC and a reduction of PKA levels.

Group II mGluRs are critically required for the induction of electrically-induced LTD (Manahan-Vaughan, 1997, Huang et al., 1997). Furthermore, agonist activation of group II mGluRs induces LTD (Manahan-Vaughan and Reymann, 1995b, Manahan-Vaughan and Reymann, 1997). This mGluR subgroup contains the receptors mGluR2 and mGluR3. Whereas mGluR2 is present only on neurones, the mGluR3 receptor is of particular interest since it is the only mGluR subtype which is expressed on glial cells in addition to neurons in adult animals (Tanabe et al., 1993, Ohishi et al., 1993, Ghose et al., 1997). Activation of mGluR3 on neurones leads to enhanced expression of GABA receptor subunits (Ghose et al., 1997), whereas activation of astrocytic mGluR3 induces increased expression of the glutamate transporters, GLAST and GLT-1 (Aronica et al., 2003). This suggests that mGluR3 may be of marked significance in the regulation of excitability in neuronal networks, as well as of synaptic plasticity. It has been shown previously that the mGluR3 receptor is selectively involved in the expression of electrically-induced LTD in vivo (Pöschel et al., in press) and chemically-induced LTD in vitro (Huang et al., 1999a). MGluR3-induced LTD has not been characterised in the intact animal.

Whereas substantial information exists about the intracellular signal cascades which mediate electrically-induced LTD (Kemp and Bashir, 2001, Braunewell and Manahan-Vaughan, 2001), much less is known about the cellular mechanisms of mGluR-induced LTD (Schnabel et al., 1999, Huang et al., 1999b, Huber et al., 2000; Naie and Manahan-Vaughan, 2003). In the present study, we therefore investigated the mechanisms underlying LTD induced by group II mGluR activation, with particular focus on the group II mGluR subtype, mGluR3.

Section snippets

Surgical preparation

Seven-to-eight-week-old male Wistar rats underwent implantation of a bipolar stimulating electrode and monopolar recording electrode (made from 0.1-mm diameter Teflon-coated stainless steel wire) into the medial perforant path and the dentate gyrus granule cell layer, respectively, as described previously (Manahan-Vaughan and Reymann, 1995a, Manahan-Vaughan and Reymann, 1995b). Briefly, under sodium pentobarbitone anaesthesia (Nembutal, 40 mg/kg, i.p., Serva, Germany) a hole was drilled in the

Group II mGluR activation induces a long-lasting depression in the dentate gyrus

It was shown previously that agonist activation of group II mGluRs induces a long-lasting depression in area CA1 of the hippocampus in vivo (Manahan-Vaughan and Reymann, 1997). In this study we investigated if the group II mGluR subtype mGluR3 contributes to this form of plasticity.

As a first step we compared responses elicited by application of the general group II mGluR agonist 4C3HPG, with responses evoked by NAAG-application. Treatment with 4C3HPG produces robust depression in vivo (

Discussion

The present study demonstrates for the first time that agonist activation of the mGluR3 receptor induces a long-lasting depression of synaptic transmission in the intact animal. This form of LTD does not depend on activation of NMDA receptors. L-type voltage-gated Ca2+-channels (VGCCs) do not appear to be directly involved. Intriguingly, group II mGluR-induced LTD as well as mGluR3-induced LTD were not affected by the inhibition of mRNA- or protein synthesis. This suggests that mGluR-mediated

Overview

The present study demonstrated that agonist activation of group II mGluRs or mGluR3 results in a long-lasting depression of synaptic transmission in the dentate gyrus of freely moving rats. This effect is distinct from persistent electrically-induced LTD that is group II mGluR-dependent (Manahan-Vaughan, 1997). The later form of LTD is NMDA receptor-dependent (Manahan-Vaughan, 1997) and requires activation of voltage-gated calcium channels (Wang et al., 1997). Taken together, these findings

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft grant Ma 1843 to DMV.

References (74)

  • D.E. Jane et al.

    Potent antagonists at L-AP4- and (1S,3S)-ACPD-sensitive presynaptic metabotropic glutamate receptors in neonatal rat spinal cord

    Neuropharmacology

    (1996)
  • K. Kameyama et al.

    Involvement of a postsynaptic protein kinase A substrate in the expression of homosynaptic long-term depression

    Neuron

    (1998)
  • N. Kemp et al.

    Long-term depression: a cascade of induction and expression mechanisms

    Prog. Neurobiol.

    (2001)
  • H.K. Lee et al.

    NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus

    Neuron

    (1998)
  • G. Losi et al.

    NAAG fails to antagonize synaptic and extrasynaptic NMDA receptors in cerebellar granule neurons

    Neuropharmacology

    (2004)
  • D. Manahan-Vaughan et al.

    Regional and developmental profile of modulation of hippocampal synaptic transmission and LTP by AP4-sensitive mGluRs in vivo

    Neuropharmacology

    (1995)
  • D. Manahan-Vaughan et al.

    1S,3R-ACPD dose dependently induces a slow onset potentiation in the dentate gyrus in vivo

    Eur. J. Pharmacol.

    (1995)
  • D. Manahan-Vaughan et al.

    Group 1 metabotropic glutamate receptors contribute to slow-onset potentiation in the rat CA1 region in vivo

    Neuropharmacology

    (1997)
  • D. Manahan-Vaughan

    Priming of group 2 metabotropic glutamate receptors facilitates induction of long-term depression in the dentate gyrus of freely moving rats

    Neuropharmacology

    (1998)
  • D. Manahan-Vaughan et al.

    Subtype-specific involvement of metabotropic glutamate receptors in two forms of long-term potentiation in the dentate gyrus of freely moving rats

    Neuroscience

    (1998)
  • Y. Nakajima et al.

    Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for l-2-amino-4-phosphonobutyrate

    J. Biol. Chem.

    (1993)
  • N. Okamoto et al.

    Molecular characterization of a new metabotropic glutamate receptor mGluR7 coupled to inhibitory cyclic AMP signal transduction

    J. Biol. Chem.

    (1994)
  • S.M. O'Mara et al.

    Metabotropic glutamate receptor-induced homosynaptic long-term depression and depotentiation in the dentate gyrus of the rat hippocampus in vitro

    Neuropharmacology

    (1995)
  • M.J. Palmer et al.

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

    Neuropharmacology

    (1997)
  • K.W. Roche et al.

    Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit

    Neuron

    (1996)
  • M. Scanziani et al.

    Presynaptic inhibition of excitatory synaptic transmission by muscarinic and metabotropic glutamate receptor activation in the hippocampus: are Ca2+ channels involved?

    Neuropharmacology

    (1995)
  • R. Schnabel et al.

    An investigation into signal transduction mechanisms involved in DHPG-induced LTD in the CA1 region of the hippocampus

    Neuropharmacology

    (1999)
  • E. Shave et al.

    Regional distribution and pharmacological characteristics of [3H]N-acetyl-aspartyl-glutamate (NAAG) binding sites in rat brain

    Neurochem. Int.

    (2001)
  • Y. Tanabe et al.

    A family of metabotropic glutamate receptors

    Neuron

    (1992)
  • B.L. Trommer et al.

    Long-term depression at the medial perforant path–granule cell synapse in developing rat dentate gyrus

    Brain Res. Dev. Brain Res.

    (1996)
  • E. Aronica et al.

    Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins

    Eur. J. Neurosci.

    (2003)
  • C.P. Bailey et al.

    Pairing elevation of [cyclic GMP] with inhibition of PKA produces long-term depression of glutamate release from isolated rat hippocampal presynaptic terminals

    Eur. J. Neurosci.

    (2003)
  • T.G. Banke et al.

    Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase

    J. Neurosci.

    (2000)
  • R. Bergeron et al.

    NAAG reduces NMDA receptor current in CA1 hippocampal pyramidal neurons of acute slices and dissociated neurons

    Neuropsychopharmacology

    (2005)
  • R.D. Blakely et al.

    Hydrolysis of the brain dipeptide N-acetyl-l-aspartyl-l-glutamate: subcellular and regional distribution, ontogeny, and the effect of lesions on N-acetylated-alpha-linked acidic dipeptidase activity

    J. Neurochem.

    (1988)
  • V.Y. Bolshakov et al.

    Postsynaptic induction and presynaptic expression of hippocampal long-term depression

    Science

    (1994)
  • K.H. Braunewell et al.

    Long-term depression: a cellular basis for learning?

    Rev. Neurosci.

    (2001)
  • Cited by (29)

    • Learning-Related Hippocampal Long-Term Potentiation and Long-Term Depression

      2017, Learning and Memory: A Comprehensive Reference
    • Role of metabotropic glutamate receptors in persistent forms of hippocampal plasticity and learning

      2013, Neuropharmacology
      Citation Excerpt :

      Here, engaging in object recognition led to the occurrence of intrinsic long-term depression (LTD) in the hippocampus of behaving mice. Metabotropic glutamate receptors are very dominant in multiple forms of hippocampal synaptic plasticity both in vivo and in vitro, ranging from slow-onset potentiation and LTP, through chemical depression and protein synthesis-dependent and -independent forms of LTD (Manahan-Vaughan and Reymann, 1995; Manahan-Vaughan, 1997; Huber et al., 2001; Naie and Manahan-Vaughan, 2004, 2005; Naie and Manahan-Vaughan, 2006; Manahan-Vaughan and Braunewell, 2005; Moult et al., 2006; Pöschel and Manahan-Vaughan, 2005; Pöschel et al., 2005). This suggests a dominant role for these receptors in synaptic information storage and hippocampus-dependent forms of memory (Table 3).

    • Selective activation of either mGlu2 or mGlu3 receptors can induce LTD in the amygdala

      2013, Neuropharmacology
      Citation Excerpt :

      However, it has been less clear whether activation of mGlu3 receptors alone can induce LTD. A putative mGlu3 receptor agonist, NAAG, has been found to induce a slowly developing LTD in the dentate gyrus (Huang et al., 1999b; Poschel and Manahan-Vaughan, 2005). In the study by Huang et al. (1999b) the effect of NAAG was mimicked by group II mGlu receptor antagonists (MCPG and EGLU), and doubts have been raised as to whether NAAG acts as a selective mGlu3 receptor agonist (Chopra et al., 2009; Fricker et al., 2009).

    View all citing articles on Scopus
    View full text