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The Journal of Neuroscience, August 15, 2001, 21(16):5925-5934

Metabotropic Glutamate Receptors 1 and 5 Differentially Regulate CA1 Pyramidal Cell Function

Guido Mannaioni¹, Michael J. Marino¹, Ornella Valenti^{1, 2}, Stephen F. Traynelis¹, and P. Jeffrey Conn³

¹ Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, ² Postdoctoral Program of Preclinical and Clinical Pharmacology, University of Catania, 95125 Catania, Italy, and ³ Department of Pharmacology, Neuroscience Division, Merck Research Laboratories, West Point, Pennsylvania 19486

The activation of group I metabotropic glutamate receptors (mGluRs) produces a variety of actions that lead to alterations in excitability and synaptic transmission in the CA1 region of the hippocampus. The group I mGluRs, mGluR1 and mGluR5, are activated selectively by (S)-3,5-dihydroxyphenylglycine (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 subtype-selective antagonists. (S)-(+)--amino-a-methylbenzeneacetic acid (LY367385) is a potent competitive antagonist that is selective for mGluR1, whereas 2-methyl-6-(phenylethynyl)-pyridine (MPEP) is a potent noncompetitive antagonist that is selective for mGluR5. The use of these compounds in experiments with whole-cell patch-clamp recording and Ca²⁺-imaging techniques revealed that each group I mGluR subtype plays distinct roles in regulating the function of CA1 pyramidal neurons. The block of mGluR1 by LY367385 suppressed the DHPG-induced increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) and the direct depolarization of CA1 hippocampal neurons. In addition, the increase in the frequency of spontaneous IPSCs (sIPSCs) caused by the DHPG-induced depolarization of inhibitory interneurons also was blocked by LY367385, as was the DHPG-induced inhibition of transmission at the Schaffer collateralCA1 synapse. On the other hand, the block of mGluR5 by MPEP 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 both mGluR1 and mGluR5. These data suggest that mGluR1 and mGluR5 play distinct roles in the regulation of the excitability of hippocampal CA1 pyramidal neurons.

Key words: mGluR; mGluR1; mGluR5; (S)-3,5-dihydroxyphenylglycine (DHPG); (S)-(+)--amino-a-methylbenzeneaceticacid (LY367385); 2-methyl-6-(phenylethynyl)-pyridine (MPEP); I_AHP; IPSC; EPSC; hippocampus

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21165925-10$05.00/0

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