BACKGROUND AND PURPOSE: Presynaptic, release-regulating metabotropic glutamate 2 and 3 (mGlu2/3) autoreceptors exist in the CNS. They represent suitable targets for therapeutic approaches to central diseases that are typified by hyperglutamatergicity. The availability of specific ligands able to differentiate between mGlu2 and mGlu3 subunits allows us to further characterize these autoreceptors. In this study we investigated the pharmacological profile of mGlu2/3 receptors in selected CNS regions and evaluated their functions in mice with experimental autoimmune encephalomyelitis (EAE). EXPERIMENTAL APPROACH: The comparative analysis of presynaptic mGlu2/3 autoreceptors was performed by determining the effect of selective mGlu2/3 receptor agonist(s) and antagonist(s) on the release of [(3)H]-D-aspartate from cortical and spinal cord synaptosomes in superfusion. In EAE mice, mGlu2/3 autoreceptor-mediated release functions were investigated and effects of in vivo LY379268 administration on impaired glutamate release examined ex vivo. KEY RESULTS: Western blot analysis and confocal microscopy confirmed the presence of presynaptic mGlu2/3 receptor proteins. Cortical synaptosomes possessed LY541850-sensitive, NAAG-insensitive autoreceptors having low affinity for LY379268, while LY541850-insensitive, NAAG-sensitive autoreceptors with high affinity for LY379268 existed in spinal cord terminals. In EAE mice, mGlu2/3 autoreceptors completely lost their inhibitory activity in cortical, but not in spinal cord synaptosomes. In vivo LY379268 administration restored the glutamate exocytosis capability in spinal cord but not in cortical terminals in EAE mice. CONCLUSIONS AND IMPLICATIONS: We propose the existence of mGlu2-preferring and mGlu3-preferring autoreceptors in mouse cortex and spinal cord respectively. The mGlu3 -preferring autoreceptors could represent a target for new pharmacological approaches for treating demyelinating diseases.
BACKGROUND AND PURPOSE: Presynaptic, release-regulating metabotropic glutamate 2 and 3 (mGlu2/3) autoreceptors exist in the CNS. They represent suitable targets for therapeutic approaches to central diseases that are typified by hyperglutamatergicity. The availability of specific ligands able to differentiate between mGlu2 and mGlu3 subunits allows us to further characterize these autoreceptors. In this study we investigated the pharmacological profile of mGlu2/3 receptors in selected CNS regions and evaluated their functions in mice with experimental autoimmune encephalomyelitis (EAE). EXPERIMENTAL APPROACH: The comparative analysis of presynaptic mGlu2/3 autoreceptors was performed by determining the effect of selective mGlu2/3 receptor agonist(s) and antagonist(s) on the release of [(3)H]-D-aspartate from cortical and spinal cord synaptosomes in superfusion. In EAE mice, mGlu2/3 autoreceptor-mediated release functions were investigated and effects of in vivo LY379268 administration on impaired glutamate release examined ex vivo. KEY RESULTS: Western blot analysis and confocal microscopy confirmed the presence of presynaptic mGlu2/3 receptor proteins. Cortical synaptosomes possessed LY541850-sensitive, NAAG-insensitive autoreceptors having low affinity for LY379268, while LY541850-insensitive, NAAG-sensitive autoreceptors with high affinity for LY379268 existed in spinal cord terminals. In EAE mice, mGlu2/3 autoreceptors completely lost their inhibitory activity in cortical, but not in spinal cord synaptosomes. In vivo LY379268 administration restored the glutamate exocytosis capability in spinal cord but not in cortical terminals in EAE mice. CONCLUSIONS AND IMPLICATIONS: We propose the existence of mGlu2-preferring and mGlu3-preferring autoreceptors in mouse cortex and spinal cord respectively. The mGlu3 -preferring autoreceptors could represent a target for new pharmacological approaches for treating demyelinating diseases.
Authors: Lydia Hanna; Laura Ceolin; Sarah Lucas; James Monn; Bryan Johnson; Graham Collingridge; Zuner Bortolotto; David Lodge Journal: Neuropharmacology Date: 2012-03-15 Impact factor: 5.250
Authors: Kristen A Rahn; Crystal C Watkins; Jesse Alt; Rana Rais; Marigo Stathis; Inna Grishkan; Ciprian M Crainiceau; Martin G Pomper; Camilo Rojas; Mikhail V Pletnikov; Peter A Calabresi; Jason Brandt; Peter B Barker; Barbara S Slusher; Adam I Kaplin Journal: Proc Natl Acad Sci U S A Date: 2012-11-19 Impact factor: 11.205
Authors: James A Monn; Lourdes Prieto; Lorena Taboada; Concepcion Pedregal; Junliang Hao; Matt R Reinhard; Steven S Henry; Paul J Goldsmith; Christopher D Beadle; Lesley Walton; Teresa Man; Helene Rudyk; Barry Clark; David Tupper; S Richard Baker; Carlos Lamas; Carlos Montero; Alicia Marcos; Jaime Blanco; Mark Bures; David K Clawson; Shane Atwell; Frances Lu; Jing Wang; Marijane Russell; Beverly A Heinz; Xushan Wang; Joan H Carter; Chuanxi Xiang; John T Catlow; Steven Swanson; Helen Sanger; Lisa M Broad; Michael P Johnson; Kelly L Knopp; Rosa M A Simmons; Bryan G Johnson; David B Shaw; David L McKinzie Journal: J Med Chem Date: 2015-02-05 Impact factor: 7.446
Authors: Pia Irene Anna Rossi; Ilaria Musante; Maria Summa; Anna Pittaluga; Laura Emionite; Masami Ikehata; Maria Pia Rastaldi; Roberto Ravazzolo; Aldamaria Puliti Journal: Cereb Cortex Date: 2012-07-12 Impact factor: 5.357