title: Sustained Gq-Protein Signaling Disrupts Striatal Circuits via JNK.
abstract: The dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. The functionality of striatal neurons is tightly controlled by various metabotropic receptors. Whereas the Gs/Gi-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of Gq-protein-dependent signals remain poorly understood. Here, using different experimental approaches, especially designer receptor exclusively activated by designer drug (DREADD) chemogenetic technology, we found that sustained activation of Gq-protein signaling impairs the functionality of striatal neurons and we unveil the precise molecular mechanism underlying this process: a phospholipase C/Ca2+/proline-rich tyrosine kinase 2/cJun N-terminal kinase pathway. Moreover, engagement of this intracellular signaling route was functionally active in the mouse dorsal striatum in vivo, as proven by the disruption of neuronal integrity and behavioral tasks. To analyze this effect anatomically, we manipulated Gq-protein-dependent signaling selectively in neurons belonging to the direct or indirect striatal pathway. Acute Gq-protein activation in direct-pathway or indirect-pathway neurons produced an enhancement or a decrease, respectively, of activity-dependent parameters. In contrast, sustained Gq-protein activation impaired the functionality of direct-pathway and indirect-pathway neurons and disrupted the behavioral performance and electroencephalography-related activity tasks controlled by either anatomical framework. Collectively, these findings define the molecular mechanism and functional relevance of Gq-protein-driven signals in striatal circuits under normal and overactivated states.
  
  
  
  The dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. Whereas the Gs/Gi-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of Gq-protein-dependent signals remain unclear. Here, we show that striatal circuits can be "turned on" by acute Gq-protein signaling or "turned off" by sustained Gq-protein signaling. Specifically, sustained Gq-protein signaling inactivates striatal neurons by an intracellular pathway that relies on cJun N-terminal kinase. Overall, this study sheds new light onto the molecular mechanism and functional relevance of Gq-protein-driven signals in striatal circuits under normal and overactivated states.
authors.affiliation: Department of Biochemistry and Molecular Biology I, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain, and mguzman@quim.ucm.es luigi.bellocchio@inserm.fr.
authors.forename: Luigi
authors.identifier: 0000-0001-7774-3935
authors.initials: L
authors.lastname: Bellocchio
authors.affiliation: Department of Biochemistry and Molecular Biology I, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain, and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ruiz-Calvo
authors.affiliation: Department of Biochemistry and Molecular Biology I, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain, and.
authors.forename: Anna
authors.initials: A
authors.lastname: Chiarlone
authors.affiliation: Institute of Cognitive and Integrative Neuroscience of Aquitaine, University of Bordeaux, 33615 Pessac Cedex, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Cabanas
authors.affiliation: Department of Biochemistry and Molecular Biology I, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain, and.
authors.forename: Eva
authors.initials: E
authors.lastname: Resel
authors.affiliation: Institute of Cognitive and Integrative Neuroscience of Aquitaine, University of Bordeaux, 33615 Pessac Cedex, France.
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Cazalets
authors.affiliation: Department of Biochemistry and Molecular Biology I, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain, and.
authors.forename: Cristina
authors.initials: C
authors.lastname: Blázquez
authors.affiliation: Institute of Cognitive and Integrative Neuroscience of Aquitaine, University of Bordeaux, 33615 Pessac Cedex, France.
authors.forename: Yoon H
authors.initials: YH
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Molecular Biology I, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain, and.
authors.forename: Ismael
authors.identifier: 0000-0003-3501-2434
authors.initials: I
authors.lastname: Galve-Roperh
authors.affiliation: Department of Biochemistry and Molecular Biology I, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain, and mguzman@quim.ucm.es luigi.bellocchio@inserm.fr.
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology; D004569:Electroencephalography; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000502:physiology*; D009434:Neural Pathways / Q000502:physiology*; D011597:Psychomotor Performance / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013028:Space Perception / Q000502:physiology; D010738:Type C Phospholipases / Q000502:physiology
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: G-protein-coupled receptor; cJun N-terminal kinase; medium spiny neuron; striatal circuit