NMDA receptor dependence of mGlu‐mediated depression of synaptic transmission in the CA1 region of the rat hippocampus

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Abstract
1 The depression of synaptic transmission by the specific metabotropic glutamate receptor (mGlu) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3R)-ACPD) was investigated in area CA1 of the hippocampus of 4–10 week old rats, by use of grease-gap and intracellular recording techniques. 2 In the presence of 1 mM Mg2+, (1S,3R)-ACPD was a weak synaptic depressant. In contrast, in the absence of added Mg2+, (1S,3R)-ACPD was much more effective in depressing both the α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptormediated components of synaptic transmission. At 100 μm, (1S,3R)-ACPD depressed the slope of the field excitatory postsynaptic potential (e.p.s.p.) by 96 ± 1% (mean ± s.e.mean; n = 7) compared with 23 ± 4% in 1 mM Mg2+-containing medium (n = 17). 3 The depressant action of 100 μm (1S,3R)-ACPD in Mg2+-free medium was reduced from 96 ± 1 to 46 ± 6% (n = 7) by the specific NMDA receptor antagonist (R)-2-amino-5-phosphonopentanoate (AP5; 100 μm). 4 Blocking both components of GABA receptor-mediated synaptic transmission with picrotoxin (50 μm) and CGP 55845A (1 μm) in the presence of 1 mM Mg2+ also enhanced the depressant action of (1S,3R)-ACPD (100 μm) from 29 ± 5 to 67 ± 6% (n = 6). 5 The actions of (1S,3R)-ACPD, recorded in Mg2+-free medium, were antagonized by the mGlu antagonist (+)-α-methyl-4-carboxyphenylglycine ((+)-MCPG). Thus, depressions induced by 30 μm (1S,3R)-ACPD were reversed from 48 ± 4 to 8 ± 6% (n = 4) by 1 mM (+)-MCPG. 6 In Mg2+-free medium, a group I mGlu agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG; 100 μm) depressed synaptic responses by 74 ± 2% (n = 18). In contrast, neither the group II agonists ((2S,1′S,2′S)-2-(2′-carboxycyclopropyl)glycine; L-CCG-1; 10 μm; n = 4) and ((2S,1′R,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine; DCG-IV; 100 nM; n = 3) nor the group III agonist ((S)-2-amino-4-phosphonobutanoic acid; L-AP4; 10 μm; n = 4) had any effect. 7 The depolarizing action of (1S,3R)-ACPD, recorded intracellularly, was similar in the presence and absence of Mg2+. AP5 did not affect the (1S,3R)-ACPD-induced depolarization in Mg2+-free medium. Thus, 50 μm (1S,3R)-ACPD induced depolarizations of 9 ± 3 mV (n = 5), 10 ± 2 mV (n = 4) and 8 ± 2 mV (n = 5) in the three respective conditions. 8 On resetting the membrane potential in the presence of 50 μm (1S,3R)-ACPD to its initial level, the e.p.s.p. amplitude was enhanced by 8 ± 3% in 1 mM Mg2+ (n = 5) compared with a depression of 37 ± 11% in the absence of Mg2+ (n = 4). Addition of AP5 prevented the (1S,3R)-ACPD-induced depression of the e.p.s.p. (depression of 4 ± 5% (n = 5)). 9 It is concluded that activation by group 1 mGlu agonists results in a depression of excitatory synaptic transmission in an NMDA receptor-dependent manner.