Both mGluR1 and mGluR5 mediate Ca2+ release and inward currents in hippocampal CA1 pyramidal neurons

Abstract

Using combined whole-cell voltage-clamp recording and Ca2+ 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 Ca2+ levels ([Ca2+]i), within neuronal somas and apical dendrites, together with a relatively long lasting inward current (IDHPG). Both types of response were enhanced by depolarisation (−30 mV), and this condition was used for their characterisation. The DHPG-induced [Ca2+]i rise was much more sensitive to manipulations of Ca2+ homeostasis, such as using the Ca2+ store depleting agent, cyclopiazonic acid (50–100 μM), the fast Ca2+ buffer, BAPTA (intracellular; 20–40 mM) and Ca2+-free/EGTA (1 mM) bath solution, than IDHPG, suggesting that these responses are, in the main part, mediated by distinct processes. The selective mGluR1 and mGluR5 antagonists, (S)-(+)-α-amino-a-methylbenzeneacetic acid (LY367385; 100 μM) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP;10 μM), respectively, markedly inhibited both IDHPG and the DHPG-evoked increase in [Ca2+]i. Moreover, these antagonists inhibited the Ca2+ 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 Ca2+ release from intracellular stores are enhanced under depolarising conditions and that mGluR1 and mGluR5 both contribute to these phenomena.