Decreased number of striatal cholinergic interneurons and motor deficits in dopamine receptor 2-expressing-cell-specific Dyt1 conditional knockout mice

NEUROBIOLOGY OF DISEASE

卷:134

Article

Yokoi, Fumiaki¹  Oleas, Janneth¹  Xing, Hong¹  Liu, Yuning¹  Dexter, Kelly M.¹  Misztal, Carly¹  Gerard, Melinda¹  Efimenko, Iakov¹  Lynch, Patrick¹  Villanueva, Matthew¹  Alsina, Raul¹  Krishnaswamy, Shiv¹  Vaillancourt, David E.^2,3,4,5  Li, Yuqing¹ 

[1] Univ Florida, Coll Med, Dept Neurol, Norman Fixel Inst Neurol Dis, Gainesville, FL 32610 USA

[2] Univ Florida, Dept Appl Physiol & Kinesiol, Lab Rehabil Neurosci, Gainesville, FL 32611 USA

[3] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA

[4] Univ Florida, Coll Med, Dept Neurol, Gainesville, FL 32611 USA

[5] Univ Florida, Coll Med, Ctr Movement Disorders & Neurorestorat, Gainesville, FL 32611 USA

关键词: Beam walking;    Cholinergic interneuron;    Dopamine;    Drd2-Cre;    Dystonia;    DYT1;    torsinA;    TOR1A;    TrkA;    Vesicular acetylcholine transporter;   

DOI  :  10.1016/j.nbd.2019.104638

来源: Elsevier

【 摘 要 】

DYT1 early-onset generalized torsion dystonia is a hereditary movement disorder characterized by abnormal postures and repeated movements. It is caused mainly by a heterozygous trinucleotide deletion in DYT1/TOR1A, coding for torsinA. The mutation may lead to a partial loss of torsinA function. Functional alterations of the basal ganglia circuits have been implicated in this disease. Striatal dopamine receptor 2 (D2R) levels are significantly decreased in DYT1 dystonia patients and in the animal models of DYT1 dystonia. D2R-expressing cells, such as the medium spiny neurons in the indirect pathway, striatal cholinergic interneurons, and dopaminergic neurons in the basal ganglia circuits, contribute to motor performance. However, the function of torsinA in these neurons and its contribution to the motor symptoms is not clear. Here, D2R-expressing-cell-specific Dyt1 conditional knockout (d2KO) mice were generated and in vivo effects of torsinA loss in the corresponding cells were examined. The Dyt1 d2KO mice showed significant reductions of striatal torsinA, acetylcholine metabolic enzymes, Tropomyosin receptor kinase A (TrkA), and cholinergic interneurons. The Dyt1 d2KO mice also showed significant reductions of striatal D2R dimers and tyrosine hydroxylase without significant alteration in striatal monoamine contents or the number of dopaminergic neurons in the substantia nigra. The Dyt1 d2KO male mice showed motor deficits in the accelerated rotarod and beam-walking tests without overt dystonic symptoms. Moreover, the Dyt1 d2KO male mice showed significant correlations between striatal monoamines and locomotion. The results suggest that torsinA in the D2R-expressing cells play a critical role in the development or survival of the striatal cholinergic interneurons, expression of striatal D2R mature form, and motor performance. Medical interventions to compensate for the loss of torsinA function in these neurons may affect the onset and symptoms of this disease.