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

doi:10.1016/j.nbd.2021.105473

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

Neurobiol Dis. 2021 Oct:158:105473. doi: 10.1016/j.nbd.2021.105473. Epub 2021 Aug 8.

Authors

Jill R Crittenden¹, Shenyu Zhai², Magdalena Sauvage³, Takashi Kitsukawa⁴, Eric Burguière⁵, Morgane Thomsen⁶, Hui Zhang⁷, Cinzia Costa⁸, Giuseppina Martella⁹, Veronica Ghiglieri¹⁰, Barbara Picconi¹¹, Karen A Pescatore¹², Ellen M Unterwald¹², Walker S Jackson¹³, David E Housman¹⁴, S Barak Caine¹⁵, David Sulzer¹⁶, Paolo Calabresi¹⁷, Anne C Smith¹⁸, D James Surmeier², Ann M Graybiel¹⁹

Affiliations

¹ 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.
² Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
³ 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.
⁴ Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
⁵ 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.
⁶ Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and University, DK-2100, Copenhagen, Denmark; Basic Neuroscience Division, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
⁷ 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.
⁸ Neurological Clinic, Department of Medicine, Hospital Santa Maria della misericordia, University of Perugia, 06100 Perugia, Italy.
⁹ Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143 Rome, Italy.
¹⁰ San Raffaele University, 00166 Rome, Italy.
¹¹ IRCCS San Raffaele Pisana, Rome 00166, Italy.
¹² Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
¹³ Wallenberg Center for Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
¹⁴ Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
¹⁵ Basic Neuroscience Division, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
¹⁶ Departments of Psychiatry, Pharmacology, Neurology, Columbia University, New York State Psychiatric Institute, New York, NY 10032, USA.
¹⁷ 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.
¹⁸ Evelyn F. McKnight Brain Institute, University of Arizona, Tucson, AZ 85724, USA.
¹⁹ McGovern Institute for Brain Research and Dept. of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA. Electronic address: graybiel@mit.edu.

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.

Keywords: Amphetamine; Cocaine; Dendritic excitability; Drug addiction; Kir2; LTP; M1 muscarinic receptor; Self-administration; Stereotypy; Striatum.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basal Ganglia Diseases / genetics
Basal Ganglia Diseases / physiopathology
Basal Ganglia Diseases / psychology
Central Nervous System Stimulants / pharmacology
Dendrites*
Excitatory Postsynaptic Potentials / genetics
Guanine Nucleotide Exchange Factors / genetics*
Hyperkinesis / genetics
Hyperkinesis / psychology
Long-Term Potentiation
Male
Mice
Mice, Knockout
Motor Activity
Neostriatum / physiopathology*
Neuronal Plasticity*
Parasympathetic Nervous System / physiopathology*
Polymorphism, Single Nucleotide
Receptor, Muscarinic M1 / genetics
Receptor, Muscarinic M1 / physiology
Substance-Related Disorders / genetics
Substance-Related Disorders / physiopathology
Substance-Related Disorders / psychology
Synapses*

Substances

Central Nervous System Stimulants
Guanine Nucleotide Exchange Factors
Rasgrp2 protein, mouse
Receptor, Muscarinic M1

Abstract

Publication types

MeSH terms

Substances

Grants and funding