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Original Article

Korean J Physiol Pharmacol 2022; 26(6): 531-540

Published online November 1, 2022 https://doi.org/10.4196/kjpp.2022.26.6.531

Copyright © Korean J Physiol Pharmacol.

Group 1 metabotropic glutamate receptor 5 is involved in synaptically-induced Ca2+-spikes and cell death in cultured rat hippocampal neurons

Ji Seon Yang1,2, Sujeong Jeon1,2, Hyun-Jong Jang1,2, and Shin Hee Yoon1,2,*

1Department of Physiology, College of Medicine, The Catholic University of Korea, 2Catholic Neuroscience Institute, The Catholic University of Korea, Seoul 06591, Korea

Correspondence to:Shin Hee Yoon
E-mail: s-hyoon@catholic.ac.kr

Author contributions: S.H.Y. designed this research. J.S.Y. and S.J. conducted experiments. J.S.Y., S.J., andH.J.J. performed data analysis. J.S.Y., S.J., and S.H.Y. wrote the manuscript.

Received: July 22, 2022; Revised: October 14, 2022; Accepted: October 14, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Group 1 metabotropic glutamate receptors (mGluRs) can positively affect postsynaptic neuronal excitability and epileptogenesis. The objective of the present study was to determine whether group 1 mGluRs might be involved in synaptically-induced intracellular free Ca2+ concentration ([Ca2+]i) spikes and neuronal cell death induced by 0.1 mM Mg2+ and 10 µM glycine in cultured rat hippocampal neurons from embryonic day 17 fetal Sprague–Dawley rats using imaging methods for Ca2+ and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays for cell survival. Reduction of extracellular Mg2+ concentration ([Mg2+]o) to 0.1 mM induced repetitive [Ca2+]i spikes within 30 sec at day 11.5. The mGluR5 antagonist 6-Methyl-2-(phenylethynyl) pyridine (MPEP) almost completely inhibited the [Ca2+]i spikes, but the mGluR1 antagonist LY367385 did not. The group 1 mGluRs agonist, 3,5-dihydroxyphenylglycine (DHPG), significantly increased the [Ca2+]i spikes. The phospholipase C inhibitor U73122 significantly inhibited the [Ca2+]i spikes in the absence or presence of DHPG. The IP3 receptor antagonist 2-aminoethoxydiphenyl borate or the ryanodine receptor antagonist 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate also significantly inhibited the [Ca2+]i spikes in the absence or presence of DHPG. The TRPC channel inhibitors SKF96365 and flufenamic acid significantly inhibited the [Ca2+]i spikes in the absence or presence of DHPG. The mGluR5 antagonist MPEP significantly increased the neuronal cell survival, but mGluR1 antagonist LY367385 did not. These results suggest a possibility that mGluR5 is involved in synaptically-induced [Ca2+]i spikes and neuronal cell death in cultured rat hippocampal neurons by releasing Ca2+ from IP3 and ryanodine-sensitive intracellular stores and activating TRPC channels.

Keywords: Calcium spike, Hippocampus, IP3 receptor, Magnesium, Metabotropic glutamate receptor