Aura C Meirsman1, Julie Le Merrer2, Lucie P Pellissier3, Jorge Diaz4, Daniel Clesse5, Brigitte L Kieffer6, Jérôme A J Becker2. 1. Département de Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U-964, National de la Recherche Scientifique UMR-7104, Université de Strasbourg, Illkirch, France. 2. Département de Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U-964, National de la Recherche Scientifique UMR-7104, Université de Strasbourg, Illkirch, France.; Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique UMR-0085, National de la Recherche Scientifique UMR-7247, Université François Rabelais de Tours, Nouzilly, France. 3. Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique UMR-0085, National de la Recherche Scientifique UMR-7247, Université François Rabelais de Tours, Nouzilly, France. 4. Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale UMR-894 - Université Paris Descartes, Paris, France. 5. Département de Neurobiologie des rythmes, Institut des Neurosciences Cellulaires et Intégratives, National de la Recherche Scientifique UPR-3212, Université de Strasbourg, Strasbourg, France. 6. Département de Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U-964, National de la Recherche Scientifique UMR-7104, Université de Strasbourg, Illkirch, France.. Electronic address: Brigitte.Kieffer@douglas.mcgill.ca.
Abstract
BACKGROUND: GPR88 is an orphan G protein coupled receptor highly enriched in the striatum, and previous studies have focused on GPR88 function in striatal physiology. The receptor is also expressed in other brain areas, and here we examined whether GPR88 function extends beyond striatal-mediated responses. METHODS: We created Gpr88 knockout mice and examined both striatal and extrastriatal regions at molecular and cellular levels. We also tested striatum-, hippocampus-, and amygdala-dependent behaviors in Gpr88(-/-) mice using extensive behavioral testing. RESULTS: We found increased G protein coupling for delta opioid receptor (DOR) and mu opioid, but not other Gi/o coupled receptors, in the striatum of Gpr88 knockout mice. We also found modifications in gene transcription, dopamine and serotonin contents, and dendritic morphology inside and outside the striatum. Behavioral testing confirmed striatal deficits (hyperactivity, stereotypies, motor impairment in rotarod). In addition, mutant mice performed better in spatial tasks dependent on hippocampus (Y-maze, novel object recognition, dual solution cross-maze) and also showed markedly reduced levels of anxiety (elevated plus maze, marble burying, novelty suppressed feeding). Strikingly, chronic blockade of DOR using naltrindole partially improved motor coordination and normalized spatial navigation and anxiety of Gpr88(-/-) mice. CONCLUSIONS: We demonstrate that GPR88 is implicated in a large repertoire of behavioral responses that engage motor activity, spatial learning, and emotional processing. Our data also reveal functional antagonism between GPR88 and DOR activities in vivo. The therapeutic potential of GPR88 therefore extends to cognitive and anxiety disorders, possibly in interaction with other receptor systems.
BACKGROUND:GPR88 is an orphan G protein coupled receptor highly enriched in the striatum, and previous studies have focused on GPR88 function in striatal physiology. The receptor is also expressed in other brain areas, and here we examined whether GPR88 function extends beyond striatal-mediated responses. METHODS: We created Gpr88 knockout mice and examined both striatal and extrastriatal regions at molecular and cellular levels. We also tested striatum-, hippocampus-, and amygdala-dependent behaviors in Gpr88(-/-) mice using extensive behavioral testing. RESULTS: We found increased G protein coupling for delta opioid receptor (DOR) and mu opioid, but not other Gi/o coupled receptors, in the striatum of Gpr88 knockout mice. We also found modifications in gene transcription, dopamine and serotonin contents, and dendritic morphology inside and outside the striatum. Behavioral testing confirmed striatal deficits (hyperactivity, stereotypies, motor impairment in rotarod). In addition, mutant mice performed better in spatial tasks dependent on hippocampus (Y-maze, novel object recognition, dual solution cross-maze) and also showed markedly reduced levels of anxiety (elevated plus maze, marble burying, novelty suppressed feeding). Strikingly, chronic blockade of DOR using naltrindole partially improved motor coordination and normalized spatial navigation and anxiety of Gpr88(-/-) mice. CONCLUSIONS: We demonstrate that GPR88 is implicated in a large repertoire of behavioral responses that engage motor activity, spatial learning, and emotional processing. Our data also reveal functional antagonism between GPR88 and DOR activities in vivo. The therapeutic potential of GPR88 therefore extends to cognitive and anxiety disorders, possibly in interaction with other receptor systems.
Authors: Claire Gaveriaux-Ruff; Chihiro Nozaki; Xavier Nadal; Xavier C Hever; Raphael Weibel; Audrey Matifas; David Reiss; Dominique Filliol; Mohammed A Nassar; John N Wood; Rafael Maldonado; Brigitte L Kieffer Journal: Pain Date: 2011-02-03 Impact factor: 6.961
Authors: Md Toufiqur Rahman; Ann M Decker; Tiffany L Langston; Kelly M Mathews; Lucas Laudermilk; Rangan Maitra; Weiya Ma; Emmanuel Darcq; Brigitte L Kieffer; Chunyang Jin Journal: J Med Chem Date: 2020-11-18 Impact factor: 7.446
Authors: Tanzil Mahmud Arefin; Anna E Mechling; Aura Carole Meirsman; Thomas Bienert; Neele Saskia Hübner; Hsu-Lei Lee; Sami Ben Hamida; Aliza Ehrlich; Dan Roquet; Jürgen Hennig; Dominik von Elverfeldt; Brigitte Lina Kieffer; Laura-Adela Harsan Journal: Brain Connect Date: 2017-10