PHARMACOLOGY OF POSTSYNAPTIC METABOTROPIC GLUTAMATE RECEPTORS IN RAT HIPPOCAMPAL CA1 PYRAMIDAL NEURONS

1 Activation of metabotropic glutamate receptors (mGluRs) in hippocamp al CA1 pyramidal neurones leads to a depolarization, an increase in in put resistance and a reduction in spike frequency adaptation (or accom modation). At least eight subtypes of mGluR have been identified which have been divided into three groups based on their biochemical, struc tural and pharmacological properties. It is unclear to which group the mGluRs which mediate these excitatory effects in hippocampal CA1 pyra midal neurones belong. We have attempted to address this question by u sing intracellular recording to test the effects of a range of mGluR a gonists and antagonists, that exhibit different profiles of subtype sp ecificity, on the excitability of CAI pyramidal neurones in rat hippoc ampal slices. 2 (2S,I'S,2'S)-2-(2'-carboxycyclopropyl)glycine (L-CCG1) caused a reduction in spike frequency adaptation and a depolarization (1-10 mV) associated with an increase in input resistance (10-30%) at concentrations (greater than or equal to 50 mu M) that have been show n to activate mGluRs in groups I, II and III. Similar effects were obs erved with concentrations (50-100 mu M) of (1S,3R)-1-aminocyclopentane -1,3-dicarboxylic acid ((IS,3R)-ACPD) and (1S,3S)-ACPD that exhibit li ttle or no activity at group III mGluRs but which activate groups I an d II mGluRs. 3 Inhibition of the release of endogenous neurotransmitte rs through activation of GABA(B) receptors, by use of 200 mu M (+/-)-b aclofen, did not alter the effects of (1S,3R)-ACPD (50-100 mu M), (1S, 3S)-ACPD (100 mu M) or L-CCG1 (100 mu M). This suggests that mGluR ago nists directly activate CA1 pyramidal neurones. 4 Like these broad spe ctrum mGluR agonists, the racemic mixture ((SR)-) or resolved (S)-isom er of the selective group I mGluR agonist 3,5-dihydroxyphenylglycine ( (SR)-DHPG (50-100 mu M) or (S)-DHPG (20-50 mu M)) caused a reduction i n spike frequency adaptation concomitant with postsynaptic depolarizat ion and an increase in input resistance. In contrast, ,1'R,2'R,3'R-2-( 2',3'-dicarboxycyclopropyl)glycine (DCG-IV; 100 mu M) and (S)-2-amino- 4-phosphonobutanoic acid (L-AP4; 100-500 mu M), which selectively acti vate group II mGluRs and group III mGluRs, respectively, had no effect on the passive membrane properties or spike frequency adaptation of C A1 pyramidal neurones. 5 The mGluR antagonists (+)-alpha-methyl-4-carb oxyphenylglycine ((+)-MCPG; 1000 mu M) and (S)-4-carboxyphenylglycine ((S)-4CPG; 1000 mu M), which block groups I and II mGluRs and group I mGluRs, respectively, had no effect on membrane potential, input resis tance or spike frequency adaptation per se. Both of these antagonists inhibited the postsynaptic effects of (IS,3R)-ACPD (50-100 mu M), (1S, 3S)-ACPD (30-100 mu M) and L-CCG1 (50-100 mu M). (+)-MCPG also reverse d the effects of (SR)-DHPG (75 mu M). (The effect of (S)-4CPG was not tested.) Their action was selective in that both antagonists did not r everse the reduction in spike frequency adaptation induced by carbacho l(1 mu M) or noradrenaline (10 mu M) whereas atropine (10 mu M) and pr opranolol (100 mu M) did. 6 From these data it is concluded that the m GluRs in CA1 pyramidal neurones responsible for these excitatory effec ts are similar to the mGluRs expressed by non-neuronal cells transfect ed with cDNA encoding group I mGluRs.