NMDA RECEPTOR DEPENDENCE OF MGLU-MEDIATED DEPRESSION OF SYNAPTIC TRANSMISSION IN THE CA1 REGION OF THE RAT HIPPOCAMPUS

1 The depression of synaptic transmission by the specific metabotropic glutamate receptor (mGlu) agonist (1S,3R)-1-aminocyclopentane-1,3-dic arboxylate ((1S,3R)-ACPD) was investigated in area CA1 of the hippocam pus of 4-10 week old rats, by use of grease-gap and intracellular reco rding techniques. 2 In the presence of 1 mM Mg2+, (1S,3R)-ACPD was a w eak synaptic depressant. In contrast, in the absence of added Mg2+, (1 S,3R)-ACPD was much more effective in depressing both the pha-amino-3- hydroxy-5-methylisoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated components of synaptic transmission. At 100 mu M, (1S,3R)-ACPD depressed the slope of the held excitatory postsyna ptic potential (e.p.s.p.) by 96 +/- 1% (mean +/- s.e. mean; n = 7) com pared with 23 +/- 4% in 1 mM Mg2+-containing medium (n = 17). 3 The de pressant action of 100 mu M (1S,3R)-ACPD in Mg2+-free medium was reduc ed from 96 +/- 1 to 46 +/- 6% (n = 7) by the specific NMDA receptor an tagonist (R)-2-amino-5-phosphonopentanoate (AP5; 100 mu M). 4 Blocking both components of GABA receptor-mediated synaptic transmission with picrotoxin (50 mu M) and CGP 55845A (1 mu M) in the presence of 1 mM M g2+ also enhanced the depressant action of (1S,3R)-ACPD (100 mu M) fro m 29 +/- 5 to 67 +/- 6% (n = 6). 5 The actions of (1S,3R)-ACPD, record ed in Mg2+-free medium, were antagonized by the mGlu antagonist (+)-al pha-methyl-4-carboxyphenylglycine ((+)-MCPG). Thus, depressions induce d by 30 mu M (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 mu M) depressed synaptic res ponses by 74 +/- 2% (n = 18). In contrast, neither the group II agonis ts ((2S,1'S,2'S)-2-(2'-carboxycyclopropyl)glycine; L-CCG-1; 10 mu M; n = 4) and ((2S, '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-phosphono butanoic acid; L-AP4; 10 mu M; n = 4) had any effect. 7 The depolarizi ng action of (1S,3R)-ACPD, recorded intracellularly, was similar in th e presence and absence of Mg2+. AP5 did not affect the (1S,3R)-ACPD-in duced depolarization in Mg2+-free medium. Thus, 50 mu M (1S,3R)-ACPD i nduced 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 mu M (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 de pression of the e.p.s.p. (depression of 4 +/- 5% (n = 5)). 9 It is con cluded that activation by group 1 mGlu agonists results in a depressio n of excitatory synaptic transmission in an NMDA receptor-dependent ma nner.