CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors

Jill R. Crittenden; Shenyu Zhai; Magdalena Sauvage; Takashi Kitsukawa; Eric Burguière; Morgane Thomsen; Hui Zhang; Cinzia Costa; Giuseppina Martella; Veronica Ghiglieri; Barbara Picconi; Karen A. Pescatore; Ellen M. Unterwald; Walker S. Jackson; David E. Housman; S. Barak Caine; David Sulzer; Paolo Calabresi; Anne C. Smith; D. James Surmeier; Ann M. Graybiel

Neurobiology of Disease (Oct 2021)

CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors

Jill R. Crittenden,
Shenyu Zhai,
Magdalena Sauvage,
Takashi Kitsukawa,
Eric Burguière,
Morgane Thomsen,
Hui Zhang,
Cinzia Costa,
Giuseppina Martella,
Veronica Ghiglieri,
Barbara Picconi,
Karen A. Pescatore,
Ellen M. Unterwald,
Walker S. Jackson,
David E. Housman,
S. Barak Caine,
David Sulzer,
Paolo Calabresi,
Anne C. Smith,
D. James Surmeier,
Ann M. Graybiel

Affiliations

Jill R. Crittenden: 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
Shenyu Zhai: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Magdalena Sauvage: 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
Takashi Kitsukawa: Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
Eric Burguière: 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
Morgane Thomsen: Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and University, DK-2100, Copenhagen, Denmark; Basic Neuroscience Division, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA
Hui Zhang: 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
Cinzia Costa: Neurological Clinic, Department of Medicine, Hospital Santa Maria della misericordia, University of Perugia, 06100 Perugia, Italy
Giuseppina Martella: Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143 Rome, Italy
Veronica Ghiglieri: San Raffaele University, 00166 Rome, Italy
Barbara Picconi: IRCCS San Raffaele Pisana, Rome 00166, Italy
Karen A. Pescatore: Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
Ellen M. Unterwald: Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
Walker S. Jackson: Wallenberg Center for Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
David E. Housman: Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
S. Barak Caine: Basic Neuroscience Division, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA
David Sulzer: Departments of Psychiatry, Pharmacology, Neurology, Columbia University, New York State Psychiatric Institute, New York, NY 10032, USA
Paolo Calabresi: 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
Anne C. Smith: Evelyn F. McKnight Brain Institute, University of Arizona, Tucson, AZ 85724, USA
D. James Surmeier: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Ann M. Graybiel: McGovern Institute for Brain Research and Dept. of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Corresponding author at: McGovern Institute for Brain Research and Dept. of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA.

Journal volume & issue: Vol. 158
p. 105473

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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