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 SurmeierAnn M. Graybiel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number105473
JournalNeurobiology of Disease
Volume158
DOIs
StatePublished - Oct 2021

Keywords

  • Amphetamine
  • Cocaine
  • Dendritic excitability
  • Drug addiction
  • Kir2
  • LTP
  • M1 muscarinic receptor
  • Self-administration
  • Stereotypy
  • Striatum

ASJC Scopus subject areas

  • Neurology

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