Both mGluR1 and mGluR5 mediate Ca super(2+) release and inward currents in hippocampal CA1 pyramidal neurons

Using combined whole-cell voltage-clamp recording and Ca super(2+) imaging we have investigated further the characteristics and pharmacology of group I metabotropic L-glutamate receptor (mGluR)-mediated responses in CA1 pyramidal neurons of the rat hippocampus. The selective group I mGluR agonist, (RS)-3, 5-dihydroxyphenylglycine (DHPG), evoked a transient increase in intracellular Ca super(2+) levels ([Ca super(2+)] sub(i)), within neuronal somas and apical dendrites, together with a relatively long lasting inward current (I sub(DHPG)). Both types of response were enhanced by depolarisation (-30 mV), and this condition was used for their characterisation. The DHPG-induced [Ca super(2+)] sub(i) rise was much more sensitive to manipulations of Ca super(2+) homeostasis, such as using the Ca super(2+) store depleting agent, cyclopiazonic acid (50-100 mu M), the fast Ca super(2+) buffer, BAPTA (intracellular; 20-40 mM) and Ca super(2+)-free/EGTA (1 mM) bath solution, than I sub(DHPG), suggesting that these responses are, in the main part, mediated by distinct processes. The selective mGluR1 and mGluR5 antagonists, (S)-(+)- alpha -amino-a-methylbenzeneacetic acid (LY367385; 100 mu M) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP; 10 mu M), respectively, markedly inhibited both I sub(DHPG) and the DHPG-evoked increase in [Ca super(2+)] sub(i.) Moreover, these antagonists inhibited the Ca super(2+) response by more than 50% suggesting a synergistic interaction between mGluR1 and mGluR5. This study demonstrates that in CA1 pyramidal neurons group I mGluR-mediated inward currents and Ca super(2+) release from intracellular stores are enhanced under depolarising conditions and that mGluR1 and mGluR5 both contribute to these phenomena.