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

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  1. Cytokine profiling in the prefrontal cortex of Parkinson's Disease and Multiple System Atrophy patients

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  2. Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

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  3. Progression of motor axon dysfunction and ectopic Nav1.8 expression in a mouse model of Charcot-Marie-Tooth disease 1B

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  4. Fluid biomarkers in multiple system atrophy: A review of the MSA Biomarker Initiative

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  5. Changes in total cell numbers of the basal ganglia in patients with multiple system atrophy - A stereological study

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  1. Effects of ketogenic diet and ketone monoester supplement on acute alcohol withdrawal symptoms in male mice

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  2. Effects of muscarinic M1 receptor stimulation on reinforcing and neurochemical effects of cocaine in rats

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  3. Glucagon-like peptide-1 receptor regulation of basal dopamine transporter activity is species-dependent

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  • 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
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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.

Original languageEnglish
Article number105473
JournalNeurobiology of Disease
Volume158
Pages (from-to)105473
ISSN0969-9961
DOIs
Publication statusPublished - Oct 2021

    Research areas

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

ID: 67032061