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