CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors
Creators
- Jill R. Crittenden1
- Shenyu Zhai2
- Magdalena Sauvage1
- Takashi Kitsukawa3
- Eric Burguière1
- Morgane Thomsen4
- Hui Zhang5
- Cinzia Costa6
- Giuseppina Martella7
- Veronica Ghiglieri8
- Barbara Picconi9
- Karen A. Pescatore10
- Ellen M. Unterwald10
- Walker S. Jackson11
- David E. Housman12
- S. Barak Caine13
- David Sulzer5
- Paolo Calabresi14
- Anne C. Smith15
- D. James Surmeier2
- Ann M. Graybiel1
- 1. McGovern Institute for Brain Research and Dept. of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA
- 2. Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- 3. Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
- 4. Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and University, DK-2100, Copenhagen, Denmark
- 5. Departments of Psychiatry, Pharmacology, Neurology, Columbia University, New York State Psychiatric Institute, New York, NY 10032, USA
- 6. Neurological Clinic, Department of Medicine, Hospital Santa Maria della misericordia, University of Perugia, 06100 Perugia, Italy
- 7. Laboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy
- 8. San Raffaele University, 00166 Rome, Italy
- 9. IRCCS San Raffaele Pisana, Rome 00166, Italy
- 10. Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
- 11. Wallenberg Center for Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
- 12. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
- 13. Basic Neuroscience Division, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA
- 14. Neurological Clinic, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy rDepartment of Neuroscience, Faculty of Medicine, Università Cattolica del "Sacro Cuore", 00168 Rome, Italy
- 15. Evelyn F. McKnight Brain Institute, University of Arizona, Tucson, AZ 85724, USA
Description
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.
Files
Critteden2021.pdf
Files
(1.3 MB)
| Name | Size | Download all |
|---|---|---|
|
md5:f997802032315e733cfba20c2ec71800
|
1.3 MB | Preview Download |