Abstract
A variety of localization and signaling properties of eight subtypes of metabotropic glutamate receptors (mGluRs) in the brain provide glutamate an important regulatory role in many processes, including neurodegeneration and repair of neuronal damage. To identify specific subtypes of mGluRs, which are involved in neurodegeneration process, we assessed expression levels of their genes under pathophysiological conditions. Using quantitative real-time RT-PCR analysis, we studied transcription levels of mGlu2-5 and mGlu7 genes in the hippocampus after its damage by neurotoxicant trimethyltin chloride (TMT) in Wistar rats. This organotin compound is known to cause neurodegeneration in the brain, especially in the hippocampus. Morphological studies confirmed neuronal damage in CA3-CA4 subfields of the hippocampus 6 weeks after the treatment with TMT. Step-through passive avoidance test revealed memory deterioration in rat-treated TMT. Interestingly, 3 and 6 weeks after the treatment with TMT, expression levels of the mGlu2 and mGlu7 genes were not changed in comparison to the control values while expression level of mGlu4 genes was upregulated throughout the whole studied period of TMT action. The dynamics of mGlu3 gene expression revealed the existence of neuroinflammation 3 weeks after the treatment with TMT, which was further confirmed by the upregulation of cyclooxygenase-2 gene expression. The expression level of mGlu5 receptors was downregulated 6 weeks after the treatment with TMT. Our results revealed a significant role of mGlu4, mGlu5, and mGlu3 receptors in the neurodegenerative/reparative processes in the hippocampus after the treatment with TMT. Ligands of these receptor subtypes can be, therefore, considered potential therapeutic targets for prevention or reduction of neurodegeneration.
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References
Amalric M, Lopez S, Goudet C, Fisone G, Battaglia G, Nicoletti F, Pin JP, Acher FC (2013) Group III and subtype 4 metabotropic glutamate receptor agonists: discovery and pathophysiological applications in Parkinson's disease. Neuropharmacology 66:53–64. https://doi.org/10.1016/j.neuropharm.2012.05.026
Arkhipov V, Kapralova M, Pershina E, Gordon R (2014) Delayed treatments with pharmacological modulators of pre- and postsynaptic mGlu receptors rescue the hippocampus from kainate-induced neurodegeneration. Neurosci Lett 570:5–9. https://doi.org/10.1016/j.neulet.2014.04.012
Bruno V, Battaglia G, Copani A, D'Onofrio M, Di Iorio P, De Blasi A, Melchiorri D, Flor PJ, Nicoletti F (2001) Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. J Cereb Blood Flow Metab 21:1013–1033. https://doi.org/10.1097/00004647-200109000-00001
Bruno V, Caraci F, Copani A, Matrisciano F, Nicoletti F, Battaglia G (2017) The impact of metabotropic glutamate receptors into active neurodegenerative processes: a “dark side” in the development of new symptomatic treatments for neurologic and psychiatric disorders. Neuropharmacology 115:180–192. https://doi.org/10.1016/j.neuropharm.2016.04.044
Cannella M, Motolese M, Bucci D, Molinaro G, Gradini R, Bruno V, Nicoletti F, Battaglia G (2015) Changes in the expression of genes encoding for mGlu4 and mGlu5 receptors and other regulators of the indirect pathway in acute mouse models of drug-induced parkinsonism. Neuropharmacology 95:50–58. https://doi.org/10.1016/j.neuropharm.2015.02.024
Correa AMB, Guimarães JDS, Dos Santos E, Alhadas E, Kushmerick C (2017) Control of neuronal excitability by group I metabotropic glutamate receptors. Biophys Rev 9:835–845. https://doi.org/10.1007/s12551-017-0301-7
Corvino V, Marchese E, Michetti F, Geloso MC (2013) Neuroprotective strategies in hippocampal neurodegeneration induced by the neurotoxicant trimethyltin. Neurochem Res 38:240–253. https://doi.org/10.1007/s11064-012-0932-9
Domin H, Zięba B, Gołembiowska K, Kowalska M, Dziubina A, Śmiałowska M (2010) Neuroprotective potential of mGluR5 antagonist MTEP: effects on kainate-induced excitotoxicity in the rat hippocampus. Pharmacol Rep 62:1051–1061. https://doi.org/10.1016/S1734-1140(10)70367-4
Gasparini F, Di Paolo T, Gomez-Mancilla B (2013) Metabotropic glutamate receptors for Parkinson’s disease therapy. Parkinsons Dis 2013:196028. https://doi.org/10.1155/2013/196028
Geloso MC, Corvino V, Michetti F (2011) Trimethyltin-induced hippocampal degeneration as a tool to investigate neurodegenerative processes. Neurochem Int 58:729–738. https://doi.org/10.1016/j.neuint.2011.03.009
Hermans E, Challiss RAJ (2001) Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. Biochem J 359:465–484. https://doi.org/10.1042/0264-6021:3590465
Johnson GA, Calabrese E, Little PB, Hedlund L, Qi Y, Badea A (2014) Quantitative mapping of trimethyltin injury in the rat brain using magnetic resonance histology. Neurotoxicology 42:12–23. https://doi.org/10.1016/j.neuro.2014.02.009
Lattanzi W, Corvino V, Di Maria V, Michetti F, Geloso MC (2013) Gene expression profiling as a tool to investigate the molecular machinery activated during hippocampal neurodegeneration induced by trimethyltin (TMT) administration. Int J Mol Sci 14:16817–16835. https://doi.org/10.3390/ijms140816817
Lee S, Yang M, Kim J, Kang S, Kim J, Kim JC, Jung C, Shin T, Kim SH, Moon C (2016) Trimethyltin-induced hippocampal neurodegeneration: a mechanism-based review. Brain Res Bull 125:187–199. https://doi.org/10.1016/j.brainresbull.2016.07.010
Little AR, Miller DB, Li S, Kashon ML, O'Callaghan JP (2012) Trimethyltin-induced neurotoxicity: gene expression pathway analysis, q-RT-PCR and immunoblotting reveal early effects associated with hippocampal damage and gliosis. Neurotoxicol Teratol 34:72–82. https://doi.org/10.1016/j.ntt.2011.09.012
Minghetti L (2004) Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol 63:901–910. https://doi.org/10.1093/jnen/63.9.901
Moyanova SG, Mastroiacovo F, Kortenska LV, Mitreva RG, Fardone E, Santolini I, Sobrado M, Battaglia G, Bruno V, Nicoletti F, Ngomba RT (2011) Protective role for type 4 metabotropic glutamate receptors against ischemic brain damage. J Cereb Blood Flow Metab 31:1107–1118. https://doi.org/10.1038/jcbfm.2010.201
Mudo G, Trovato-Salinaro A, Caniglia G, Cheng Q, Condorelli DF (2007) Cellular localization of mGluR3 and mGluR5 mRNAs in normal and injured rat brain. Brain Res 1149:1–13. https://doi.org/10.1016/j.brainres.2007.02.041
Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP (2011) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60:1017–1041. https://doi.org/10.1016/j.neuropharm.2010.10.022
Pershina EV, Arkhipov VI (2016) Subacute activation of mGlu4 receptors causes the feedback inhibition of its gene expression in rat brain. Life Sci 153:50–54. https://doi.org/10.1016/j.lfs.2016.03.033
Pershina EV, Kapralova MV, Arkhipov VI (2017) Effect of pharmacological modulation of activity of metabotropic glutamate receptors on their gene expression after excitotoxic damage in hippocampal neurons. Bull Exp Biol Med 162:784–787. https://doi.org/10.1007/s10517-017-3713-2
Pinheiro PS, Mulle C (2008) Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nat Rev Neurosci 9:423–436. https://doi.org/10.1038/nrn2379
Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108. https://doi.org/10.1038/nprot.2008.73
Trabucco A, Di Pietro P, Nori SL, Fulceri F, Fumagalli L, Paparelli A, Fornai F (2009) Methylated tin toxicity a reappraisal using rodents models. Arch Ital Biol 147:141–153
Wong RKS, Bianchi R, Chuang S-C, Merlin LR (2005) Group I mGluR-induced epileptogenesis: distinct and overlapping roles of mGluR1 and mGluR5 and implications for antiepileptic drug design. Epilepsy Curr 5:63–68. https://doi.org/10.1111/j.1535-7597.2005.05207
Yin S, Niswender CM (2014) Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications. Cell Signal 26:2284–2297. https://doi.org/10.1016/j.cellsig.2014.04.022
Zhang S, Manahan-Vaughan D (2014) Place field stability requires the metabotropic glutamate receptor, mGlu5. Hippocampus 24:1330–1340. https://doi.org/10.1002/hipo.22314
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This work was supported by Russian Foundation for Basic Research (Grant No. 16-34-01167).
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Pershina, E.V., Mikheeva, I.B., Kamaltdinova, E.R. et al. Expression of mGlu Receptor Genes in the Hippocampus After Intoxication with Trimethyltin. J Mol Neurosci 67, 258–264 (2019). https://doi.org/10.1007/s12031-018-1233-9
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DOI: https://doi.org/10.1007/s12031-018-1233-9