CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors
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1-s2.0-S0969996121002229-main.pdf
Description
Published version
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3.27 MB
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Author(s)
Crittenden, Jill R
Zhai, Shenyu
Sauvage, Magdalena
Kitsukawa, Takashi
Burguière, Eric
Thomsen, Morgane
Zhang, Hui
Costa, Cinzia
Martella, Giuseppina
Ghiglieri, Veronica
Date Issued
October 2021
Journal
Neurobiology of Disease
Publisher
Elsevier BV
Citation
Crittenden, Jill R, Zhai, Shenyu, Sauvage, Magdalena, Kitsukawa, Takashi, Burguière, Eric et al. 2021. "CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors." Neurobiology of Disease, 158.
Version
Final published version
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.
MIT Department
McGovern Institute for Brain Research at MIT
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.nbd.2021.105473
