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CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors.
Crittenden, Jill R; Zhai, Shenyu; Sauvage, Magdalena; Kitsukawa, Takashi; Burguière, Eric; Thomsen, Morgane; Zhang, Hui; Costa, Cinzia; Martella, Giuseppina; Ghiglieri, Veronica; Picconi, Barbara; Pescatore, Karen A; Unterwald, Ellen M; Jackson, Walker S; Housman, David E; Caine, S Barak; Sulzer, David; Calabresi, Paolo; Smith, Anne C; Surmeier, D James; Graybiel, Ann M.
Affiliation
  • Crittenden JR; McGovern Institute for Brain Research and Dept. of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
  • Zhai S; Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Sauvage M; McGovern Institute for Brain Research and Dept. of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Leibniz Institute for Neurobiology, Functional Architecture of Memory Dept., Magdeburg, Germany.
  • Kitsukawa T; Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
  • Burguière E; McGovern Institute for Brain Research and Dept. of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Brain and Spine Institute (ICM), CNRS UMR 7225, INSERM U 1127, UPMC-P6 UMR S, 1127, Hôpital de la Pitié-Salpêtrière, 47 boulevard de l'hôpital, Paris, France.
  • Thomsen M; Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and University, DK-2100, Copenhagen, Denmark; Basic Neuroscience Division, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
  • Zhang H; Departments of Psychiatry, Pharmacology, Neurology, Columbia University, New York State Psychiatric Institute, New York, NY 10032, USA; Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  • Costa C; Neurological Clinic, Department of Medicine, Hospital Santa Maria della misericordia, University of Perugia, 06100 Perugia, Italy.
  • Martella G; Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143 Rome, Italy.
  • Ghiglieri V; San Raffaele University, 00166 Rome, Italy.
  • Picconi B; IRCCS San Raffaele Pisana, Rome 00166, Italy.
  • Pescatore KA; Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
  • Unterwald EM; Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
  • Jackson WS; Wallenberg Center for Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
  • Housman DE; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
  • Caine SB; Basic Neuroscience Division, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
  • Sulzer D; Departments of Psychiatry, Pharmacology, Neurology, Columbia University, New York State Psychiatric Institute, New York, NY 10032, USA.
  • Calabresi P; Neurological Clinic, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; Department of Neuroscience, Faculty of Medicine, Università Cattolica del "Sacro Cuore", 00168 Rome, Italy.
  • Smith AC; Evelyn F. McKnight Brain Institute, University of Arizona, Tucson, AZ 85724, USA.
  • Surmeier DJ; Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • Graybiel AM; McGovern Institute for Brain Research and Dept. of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA. Electronic address: graybiel@mit.edu.
Neurobiol Dis ; 158: 105473, 2021 10.
Article in En | MEDLINE | ID: mdl-34371144
ABSTRACT
CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the self-administration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGI's therapeutic potential.
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Full text: 1 Database: MEDLINE Main subject: Parasympathetic Nervous System / Synapses / Neostriatum / Guanine Nucleotide Exchange Factors / Dendrites / Neuronal Plasticity Limits: Animals Language: En Journal: Neurobiol Dis Journal subject: NEUROLOGIA Year: 2021 Type: Article Affiliation country: United States
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Full text: 1 Database: MEDLINE Main subject: Parasympathetic Nervous System / Synapses / Neostriatum / Guanine Nucleotide Exchange Factors / Dendrites / Neuronal Plasticity Limits: Animals Language: En Journal: Neurobiol Dis Journal subject: NEUROLOGIA Year: 2021 Type: Article Affiliation country: United States