Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function

The activation of group I metabotropic glutamate receptors (mGluRs) produce s a variety of actions that lead to alterations in excitability and synapti c transmission in the CA1 region of the hippocampus. The group I mGluRs, mG luR1 and mGluR5, are activated selectively by (S)-3,5-dihydroxyphenylglycin e (DHPG). To identify which of these mGluR subtypes are responsible for the various actions of DHPG in area CA1, we took advantage of two novel subtyp e-selective antagonists. (S)-(+)-alpha -amino-a-methylbenzeneacetic acid (L Y367385) is a potent competitive antagonist that is selective for mGluR1, w hereas 2-methyl-6-(phenylethynyl)-pyridine (MPEP) is a potent noncompetitiv e antagonist that is selective for mGluR5. The use of these compounds in ex periments with whole-cell patch-clamp recording and Ca2+-imaging techniques revealed that each group I mGluR subtype plays distinct roles in regulatin g the function of CA1 pyramidal neurons. The block of mGluR1 by LY367385 su ppressed the DHPG-induced increase in intracellular Ca2+ concentration ([Ca 2+](i)) and the direct depolarization of CA1 hippocampal neurons. In additi on, the increase in the frequency of spontaneous IPSCs (sIPSCs) caused by t he DHPG-induced depolarization of inhibitory interneurons also was blocked by LY367385, as was the DHPG-induced inhibition of transmission at the Scha ffer collateral-->CA1 synapse. On the other hand, the block of mGluR5 by MP EP antagonized the DHPG-induced suppression of the Ca2+-activated potassium current (I-AHP) and potentiation of the NMDA receptor. Finally, antagonism of the DHPG-induced suppression of evoked IPSCs required the blockade of b oth mGluR1 and mGluR5. These data suggest that mGluR1 and mGluR5 play disti nct roles in the regulation of the excitability of hippocampal CA1 pyramida l neurons.