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

• Published in: Neurobiology of disease Vol. 158; p. 105473
• Main Authors: Crittenden, Jill R., Zhai, Shenyu, Sauvage, Magdalena, Kitsukawa, Takashi, Burguière, Eric, Thomsen, Morgane, Zhang, Hui, Costa, Cinzia, Martella, Giuseppina, Ghiglieri, Veronica, Picconi, Barbara, Pescatore, Karen A., Unterwald, Ellen M., Jackson, Walker S., Housman, David E., Caine, S. Barak, Sulzer, David, Calabresi, Paolo, Smith, Anne C., Surmeier, D. James, Graybiel, Ann M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2021; Elsevier
• Subjects: Amphetamine; Animals; Basal Ganglia Diseases - genetics; Basal Ganglia Diseases - physiopathology; Basal Ganglia Diseases - psychology; Central Nervous System Stimulants - pharmacology; Cocaine; Dendrites; Dendritic excitability; Drug addiction; Excitatory Postsynaptic Potentials - genetics; Guanine Nucleotide Exchange Factors - genetics; Hyperkinesis - genetics; Hyperkinesis - psychology; Kir2; Life Sciences; Long-Term Potentiation; LTP; M1 muscarinic receptor; Male; Mice; Mice, Knockout; Motor Activity; Neostriatum - physiopathology; Neurobiology; Neuronal Plasticity; Neurons and Cognition; Parasympathetic Nervous System - physiopathology; Polymorphism, Single Nucleotide; Receptor, Muscarinic M1 - genetics; Receptor, Muscarinic M1 - physiology; Self-administration; Stereotypy; Striatum; Substance-Related Disorders - genetics; Substance-Related Disorders - physiopathology; Substance-Related Disorders - psychology; Synapses; Striatum; Drug addiction; Self-administration; Amphetamine; LTP; Cocaine; M1 muscarinic receptor; Kir2; Dendritic excitability; Stereotypy
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2021.105473

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. •CalDAG-GEFI mediates M1 muscarinic receptor dependent plasticity in the striatum.•CDGI mediates dendritic, but not somatic, M1Rs signaling in striatal iSPNs.•CDGI is required for full induction of long-term synaptic potentiation in iSPNs.•Mice lacking CDGI fail to show behavioral plasticity induced by M1R agonists.•Mice lacking CDGI have increased susceptibility to drugs of abuse.