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

NEUROBIOLOGY OF DISEASE

卷:158

Article

Crittenden, Jill R.^1,2,3  Zhai, Shenyu⁴  Sauvage, Magdalena^1,2,5  Kitsukawa, Takashi⁶  Burguiere, Eric^1,2,7  Thomsen, Morgane^8,18  Zhang, Hui^9,10  Costa, Cinzia¹¹  Martella, Giuseppina¹²  Ghiglieri, Veronica¹³  Picconi, Barbara¹⁴  Pescatore, Karen A.^15,16  Jackson, Walker S.¹⁷  Housman, David E.³  Caine, S. Barak¹⁸  Sulzer, David⁹  Calabresi, Paolo^19,20  Smith, Anne C.²¹  Surmeier, D. James⁴  Graybiel, Ann M.^1,2 

[1] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[2] MIT, Dept Brain & Cognit Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[3] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[4] Northwestern Univ, Feinberg Sch Med, Dept Physiol, Chicago, IL 60611 USA

[5] Leibniz Inst Neurobiol, Funct Architecture Memory Dept, Magdeburg, Germany

[6] Osaka Univ, Grad Sch Frontier Biosci, Osaka, Japan

[7] Hopl Pitie Salpetriere, UPMC P6 UMR S, INSERM U 1127, Brain & Spine Inst ICM,CNRS UMR 7225, 47 Blvd Hop, Paris, France

[8] Psychiat Ctr Copenhagen & Univ, Lab Neuropsychiat, DK-2100 Copenhagen, Denmark

[9] Columbia Univ, New York State Psychiat Inst, Dept Psychiat, Pharmacol,Neurol, New York, NY 10032 USA

[10] Thomas Jefferson Univ, Dept Neurosci, Philadelphia, PA 19107 USA

[11] Univ Perugia, Hosp Santa Maria Misericordia, Dept Med, Neurol Clin, I-06100 Perugia, Italy

[12] IRCCS Fdn Santa Lucia, Neurophysiol & Plast, Via Fosso di Fiorano 64, I-00143 Rome, Italy

[13] San Raffaele Univ, I-00166 Rome, Italy

[14] IRCCS San Raffaele Pisana, I-00166 Rome, Italy

[15] Temple Univ, Dept Pharmacol, Sch Med, Philadelphia, PA 19140 USA

[16] Temple Univ, Ctr Substance Abuse Res, Sch Med, Philadelphia, PA 19140 USA

[17] Linkoping Univ, Dept Clin & Expt Med, Wallenberg Ctr Mol Med, S-58183 Linkoping, Sweden

[18] Harvard Med Sch, Basic Neurosci Div, McLean Hosp, Belmont, MA 02478 USA

[19] Fdn Policlin Univ Agostino Gemelli IRCC, Neurol Clin, I-00168 Rome, Italy

[20] Univ Cattolica Sacro Cuore, Dept Neurosci, Fac Med, I-00168 Rome, Italy

[21] Univ Arizona, Evelyn F McKnight Brain Inst, Tucson, AZ 85724 USA

关键词: Striatum;    M1 muscarinic receptor;    Kir2;    Dendritic excitability;    Stereotypy;    Amphetamine;    Cocaine;    Drug addiction;    Self-administration;    LTP;   

DOI  :  10.1016/j.nbd.2021.105473

来源: Elsevier

【 摘 要 】

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 selfadministration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGI's therapeutic potential.