DHPG-induced LTD in area CA1 of juvenile rat hippocampus; characterisation and sensitivity to novel mGlu receptor antagonists

doi:10.1016/S0028-3908(99)00123-9

Neuropharmacology

Volume 38, Issue 10, October 1999, Pages 1577-1583

https://doi.org/10.1016/S0028-3908(99)00123-9 Get rights and content

Abstract

We have used extracellular microelectrode recording to characterise a form of long-term depression (LTD) of synaptic transmission that can be induced by metabotropic glutamate (mGlu) receptor activation in the CA1 region of the young (12–18 day old) rat hippocampus. Activation of group I mGlu receptors by the specific agonist 3,5-dihydroxyphenylglyine (DHPG) induced LTD of field excitatory postsynaptic potentials (fEPSPs). The mGlu₅ selective agonist 2-chloro-5-hydroxyphenylglycine was also capable of inducing LTD. In contrast, the group II specific agonist DCG-IV had no effect on synaptic transmission, whilst the group III receptor agonist (S)-2-amino-4-phosphonobutyrate elicited a depression that reversed fully upon agonist washout. DHPG-induced LTD could still be generated after prior saturation of electrically-induced NMDA receptor-dependent LTD. DHPG-induced LTD was reversed by tetanic stimulation comprising 100 shocks delivered at 100 Hz. A novel mGlu receptor antagonist, (RS)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid) (LY393053) that potently inhibits mGlu₁ and mGlu₅ receptors, prevented the induction of DHPG-induced LTD. Like other mGlu receptor antagonists, LY393053 also reversed pre-established DHPG-induced LTD. In contrast, a potent mGlu₁ selective antagonist (S)-2-methyl-4-carboxyphenylglycine (LY367385) did not prevent the induction of DHPG-induced LTD. In conclusion, DHPG, probably via activation of mGlu₅ receptors, is able to induce a robust form of LTD in the CA1 region of the young rat hippocampus that is mechanistically distinct from NMDA receptor-dependent homosynaptic LTD.

Introduction

The involvement of metabotropic glutamate (mGlu) receptors in the induction of various forms of long-term depression (LTD) of synaptic transmission in the CA1 region of the rat hippocampus has been an area of increasing interest in recent years (Anwyl, 1999, Bortolotto et al., 1999). ‘Low frequency’ stimulation (LFS), typically 1–5 Hz, can induce de novo LTD of glutamatergic transmission in slices prepared from young (<30 day old) rats (Dudek and Bear, 1992, Mulkey and Malenka, 1992). This form of LTD is generally not blocked by antagonists of mGlu receptors (Selig et al., 1995, Fitzjohn et al., 1998), but is dependent on activation of ionotropic N-methyl-d-aspartate (NMDA) receptors (Dudek and Bear, 1992, Mulkey and Malenka, 1992). However, in slices prepared from very young animals (Bolshakov and Siegelbaum, 1994), when the slice excitability is altered (Oliet et al., 1997), or when a paired-pulse stimulation paradigm is used (Kemp and Bashir, 1999), LTD may be dependent on mGlu receptor activation. Depotentiation is another form of LTD whereby LFS reverses previous established long-term potentiation (LTP; Barrionuevo et al., 1980, Staubli and Lynch, 1990), a phenomenon which is observed in slices prepared from both adult and immature animals. In the CA1 region of the rat hippocampus, depotentiation can be blocked by antagonists of mGlu receptors (Bashir and Collingridge, 1994, Fitzjohn et al., 1998) but may not invariably be so (Selig et al., 1995).

In addition to LTD induced by electrical stimulation, long-lasting decreases in synaptic transmission can also be induced by pharmacological activation of mGlu receptors. Thus in both the dentate gyrus of adult rats (O’Mara et al., 1995) and CA1 region of immature animals (Overstreet et al., 1997) the broad spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) induces a long-lasting decrease of excitatory synaptic transmission. In the adult CA1 region, activation of group I mGlu receptors by the selective agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) elicits a small magnitude LTD (DHPG-induced LTD) which is enhanced if the excitability of the slice is increased by either removing magnesium from the extracellular medium or by the addition of the GABA_A receptor antagonist picrotoxin (Palmer et al., 1997).

Previously we have noted that DHPG can induce a comparatively large LTD in the CA1 region of slices prepared from young (12–18 day old) rats without manipulation of slice excitability (Fitzjohn et al., 1996, Fitzjohn et al., 1998). We now provide a characterisation of this form of synaptic plasticity and have assessed its sensitivity to two novel mGlu receptor antagonists.

Section snippets

Methods

Wistar rats aged 12–18 days were killed by decapitation and the brains rapidly removed and placed in ice-cold artificial cerebrospinal fluid (aCSF). This aCSF comprised (mM): NaCl (124), NaHCO₃ (26), NaH₂PO₄ (1.25), KCl (3), CaCl₂ (2), MgSO₄ (1) and d-glucose (10), bubbled continuously with 95%O₂/5% CO₂, pH 7.4. Saggital brain slices (400 μm) were prepared using a vibroslice. The hippocampi were dissected out and placed in a submerged holding chamber. After at least 1 h recovery time, slices

Effects of selective mGlu subgroup activation on excitatory transmission

Initially, the actions of agonists specific for each of the three groups of mGlu receptors were investigated. Application of the group I mGlu receptor agonist DHPG (50 μM for 20 min) elicited a depression of synaptic transmission that persisted after washout (Fig. 1, Fig. 2). Thus during DHPG application responses decreased to 53±6% of control, and after commencing washout of DHPG responses recovered only partially and 40 min later were 80±3% of control (n=6; P<0.005). This DHPG-induced LTD

Discussion

The current study provides a pharmacological characterisation of LTD of synaptic transmission induced by mGlu receptor activation in the CA1 region of the hippocampus. Previously we (Fitzjohn et al., 1996, Fitzjohn et al., 1998) and others (Huber and Bear, 1998) have demonstrated that activation of group I receptors by the selective agonist DHPG can induce LTD in slices prepared from young rats. Now we have shown that activation of mGlu₅ receptors selectively induces LTD, using the agonist

Acknowledgements

This work was funded by the BBSRC and the MRC.

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Citation Excerpt :
The type of DHPG-LTD studied here at CA1 synapses in organotypic slices is mediated exclusively by postsynaptic alterations, as determined by the lack of any change in PPF, and is triggered exclusively by the activation of mGluR1 (see also Nadif Kasri et al., 2011). DHPG-LTD has been shown to require synaptic stimulation (Scholz et al., 2010), but consistent with a previous report (Fitzjohn et al., 1999), we found that the necessary activation could be provided by a heterosynaptic input. The development of pH-sensitive GFP derivatives has greatly facilitated the study of secretion events (Miesenböck et al., 1998).
A major mechanism contributing to synaptic plasticity involves alterations in the number of AMPA receptors (AMPARs) expressed at synapses. Hippocampal CA1 synapses, where this process has been most extensively studied, are highly heterogeneous with respect to their probability of neurotransmitter release, P(r). It is unknown whether there is any relationship between the extent of plasticity-related AMPAR trafficking and the initial P(r) of a synapse. To address this question, we induced metabotropic glutamate receptor (mGluR) dependent long-term depression (mGluR-LTD) and assessed AMPAR trafficking and P(r) at individual synapses, using SEP-GluA2 and FM4-64, respectively. We found that either pharmacological or synaptic activation of mGluR1 reduced synaptic SEP-GluA2 in a manner that depends upon P(r); this process involved an activity-dependent reduction in surface mGluR1 that selectively protects high-P(r) synapses from synaptic weakening. Consequently, the extent of postsynaptic plasticity can be pre-tuned by presynaptic activity.

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DHPG-induced LTD in area CA1 of juvenile rat hippocampus; characterisation and sensitivity to novel mGlu receptor antagonists

Abstract

Introduction

Section snippets

Methods

Effects of selective mGlu subgroup activation on excitatory transmission

Discussion

Acknowledgements

Life Sci.

Curr. Opin. Neurobiol.

Bioorg. Med. Chem. Lett.

Neuropharmacology

Neuropharmacology

Mol. Brain Res.

Neuropharmacology

Eur. J. Pharmacol.

Neuropharmacology

Neuron

Neuropharmacology

Neuron

Neuropharmacology

Neuropharmacology

Neuroscience

Neuropharmacology

Neurosci. Lett.