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The Journal of Neuroscience, August 1, 2007, 27(31):8297-8308; doi:10.1523/JNEUROSCI.1889-07.2007
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Neurobiology of Disease
The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection
Corrado Corti,1 * Giuseppe Battaglia,2 * Gemma Molinaro,2 Barbara Riozzi,2 Anna Pittaluga,3 Mauro Corsi,1 Manolo Mugnaini,1 Ferdinando Nicoletti,2,4 andValeria Bruno2,4 1Department of Biology, Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline Medicines Research Centre, 37135 Verona, Italy, 2Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy, 3Department of Experimental Medicine, Pharmacology and Toxicology Section, Center of Excellence for Biomedical Research, University of Genova, 16148 Genova, Italy, and 4Department of Human Physiology and Pharmacology, University of Rome "La Sapienza," 00185 Rome, Italy
Correspondence should be addressed to Dr. Valeria Bruno, Department of Human Physiology and Pharmacology, University of Rome "La Sapienza," Piazzale Aldo Moro 5, 00185 Roma, Italy. Email: valeria.bruno{at}uniroma1.it
Dual metabotropic glutamate 2/3 (mGlu2/3) receptor agonists have been examined with success in the clinic with positive proof of efficacy in several tests of anxiety and schizophrenia. Moreover, a large body of evidence has accumulated that these drugs have significant neuroprotective potential. An important discussion in the field deals with dissecting effects on mGlu2 versus effects on mGlu3 receptors, which is relevant for the potential use of subtype-selective agonists or allosteric activators. We addressed this issue using mGlu2 and mGlu3 receptor knock-out mice. We used mixed cultures of cortical cells in which astrocytes and neurons were plated at different times and could therefore originate from different mice. Cultures were challenged with NMDA for the induction of excitotoxic neuronal death. The mGlu2/3 receptor agonist, (–)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), was equally neuroprotective in cultures containing neurons from wild-type, mGlu2–/–, or mGlu3–/– mice. Neuroprotection was instead abolished when astrocytes lacked mGlu3 receptors, unless neuronal mGlu2 receptors were also absent. The latter condition partially restored the protective activity of LY379268. Cultures in which neurons originated from mGlu2–/– mice were also intrinsically resistant to NMDA toxicity. In in vivo experiments, systemic administration of LY379268 protected striatal neurons against NMDA toxicity in wild-type and mGlu2–/– mice but not in mGlu3–/– mice. In addition, LY379268 was protective against nigrostriatal degeneration induced by low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only in mice lacking mGlu2 receptors. We conclude that neuroprotection by mGlu2/3 receptor agonists requires the activation of astrocytic mGlu3 receptors, whereas, unexpectedly, activation of mGlu2 receptors might be harmful to neurons exposed to toxic insults.
Key words: neurotoxicity; MPTP; metabotropic glutamate receptors; neuroprotection; neurotrophic; release
Received April 26, 2007; revised June 12, 2007; accepted June 13, 2007.
Correspondence should be addressed to Dr. Valeria Bruno, Department of Human Physiology and Pharmacology, University of Rome "La Sapienza," Piazzale Aldo Moro 5, 00185 Roma, Italy. Email: valeria.bruno{at}uniroma1.it
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