Alteration of the cholinergic system and motor deficits in cholinergic neuron-specific Dyt1 knockout mice

NEUROBIOLOGY OF DISEASE

卷:154

Article

Liu, Yuning^1,2  Xing, Hong¹  Sheng, Wanhui⁴  Singh, Kyle N.¹  Korkmaz, Alexandra G.¹  Comeau, Caroline¹  Anika, Maisha¹  Ernst, Alexis¹  Yokoi, Fumiaki¹  Vaillancourt, David E.³  Frazier, Charles J.⁴  Li, Yuqing^1,2 

[1] Univ Florida, Coll Med, Dept Neurol, Norman Fixel Inst Neurol Dis, Gainesville, FL 32611 USA

[2] Univ Florida, Genet Inst, Gainesville, FL USA

[3] Univ Florida, Dept Appl Physiol & Kinesiol, Biomed Engn & Neurol, Gainesville, FL USA

[4] Univ Florida, Coll Pharm, Dept Pharmacodynam, Gainesville, FL 32610 USA

关键词: DYT1;    dystonia;    the cholinergic system;    torsinA;    ChAT;   

DOI  :  10.1016/j.nbd.2021.105342

来源: Elsevier

【 摘 要 】

Dystonia is a neurological movement disorder characterized by sustained or intermittent muscle contractions, repetitive movement, and sometimes abnormal postures. DYT1 dystonia is one of the most common genetic dystonias, and most patients carry heterozygous DYT1 ?GAG mutations causing a loss of a glutamic acid of the protein torsinA. Patients can be treated with anticholinergics, such as trihexyphenidyl, suggesting an abnormal cholinergic state. Early work on the cell-autonomous effects of Dyt1 deletion with ChI-specific Dyt1 conditional knockout mice (Dyt1 Ch1KO) revealed abnormal electrophysiological responses of striatal ChIs to muscarine and quinpirole, motor deficits, and no changes in the number or size of the ChIs. However, the Chat-cre line that was used to derive Dyt1 Ch1KO mice contained a neomycin cassette and was reported to have ectopic cre-mediated recombination. In this study, we generated a Dyt1 Ch2KO mouse line by removing the neomycin cassette in Dyt1 Ch1KO mice. The Dyt1 Ch2KO mice showed abnormal paw clenching behavior, motor coordination and balance deficits, impaired motor learning, reduced striatal choline acetyltransferase protein level, and a reduced number of striatal ChIs. Furthermore, the mutant striatal ChIs had a normal muscarinic inhibitory function, impaired quinpirole-mediated inhibition, and altered current density. Our findings demonstrate a cell-autonomous effect of Dyt1 deletion on the striatal ChIs and a critical role for the striatal ChIs and corticostriatal pathway in the pathogenesis of DYT1 dystonia.