DHPG-induced LTD in area CA1 of juvenile rat hippocampus; characterisation and sensitivity to novel mGlu receptor antagonists
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 GABAA 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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2018, Cell ReportsCitation 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).