@article{7163f9c3ce7f4481838233f09a62b87e,
title = "Characterization of the direct pathway in Dyt1 ΔGAG heterozygous knock-in mice and dopamine receptor 1-expressing-cell-specific Dyt1 conditional knockout mice",
abstract = "DYT1 dystonia is a movement disorder mainly caused by a trinucleotide deletion (ΔGAG) in DYT1 (TOR1A), coding for torsinA. DYT1 dystonia patients show trends of decreased striatal ligand-binding activities to dopamine receptors 1 (D1R) and 2 (D2R). Dyt1 ΔGAG knock-in (KI) mice, which have the corresponding ΔGAG deletion, similarly exhibit reduced striatal D1R and D2R-binding activities and their expression levels. While the consequences of D2R reduction have been well characterized, relatively little is known about the effect of D1R reduction. Here, locomotor responses to D1R and D2R antagonists were examined in Dyt1 KI mice. Dyt1 KI mice showed significantly less responsiveness to both D1R antagonist SCH 23390 and D2R antagonist raclopride. The electrophysiological recording indicated that Dyt1 KI mice showed a significantly increased paired-pulse ratio of the striatal D1R-expressing medium spiny neurons and altered miniature excitatory postsynaptic currents. To analyze the in vivo torsinA function in the D1R-expressing neurons further, Dyt1 conditional knockout (Dyt1 d1KO) mice in these neurons were generated. Dyt1 d1KO mice had decreased spontaneous locomotor activity and reduced numbers of slips in the beam-walking test. Dyt1 d1KO male mice showed abnormal gait. Dyt1 d1KO mice showed defective striatal D1R maturation. Moreover, the mutant striatal D1R-expressing medium spiny neurons had increased capacitance, decreased sEPSC frequency, and reduced intrinsic excitability. The results suggest that torsinA in the D1R-expressing cells plays an important role in the electrophysiological function and motor performance. Medical interventions to the direct pathway may affect the onset and symptoms of this disorder.",
keywords = "Direct pathway, Dopamine receptor, Dystonia, Paired-pulse facilitation, Raclopride, SCH 23390",
author = "Fumiaki Yokoi and Chen, {Huan Xin} and Janneth Oleas and Dang, {Mai Tu} and Hong Xing and Dexter, {Kelly M.} and Yuqing Li",
note = "Funding Information: This work was supported by Tyler's Hope for a Dystonia Cure, Inc., “Mini-Moonshot” Fixel-MBI Pilot Grant Mechanism for Dystonia and Related Disorders, National Institutes of Health (NS047692, NS054246, NS065273, NS072872, NS074423, NS075012, NS082244, NS111498, and NS118397), startup funds from the Lucille P. Markey Charitable Trust and Beckman Institute (UIUC), Department of Neurology (UF), Dystonia Medical Research Foundation, and Bachmann-Strauss Dystonia and Parkinson Foundation, Inc., and the Office of the Assistant Secretary of Defense for Health Affairs through the Peer-Reviewed Medical Research Program (W81XWH1810099 and W81XWH2110198). Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. Nikon A1RMPsi-STORM4.0 multiphoton/super-resolution imaging system was acquired by the MBI, Office of Research, College of Medicine, and an NIH Shared Instrumentation Grant (1S10OD020026). Funding Information: This work was supported by Tyler{\textquoteright}s Hope for a Dystonia Cure, Inc. , “Mini-Moonshot” Fixel-MBI Pilot Grant Mechanism for Dystonia and Related Disorders , National Institutes of Health ( NS047692 , NS054246 , NS065273 , NS072872 , NS074423 , NS075012 , NS082244 , NS111498 , and NS118397 ), startup funds from the Lucille P. Markey Charitable Trust and Beckman Institute (UIUC), Department of Neurology (UF), Dystonia Medical Research Foundation , and Bachmann-Strauss Dystonia and Parkinson Foundation, Inc. , and the Office of the Assistant Secretary of Defense for Health Affairs through the Peer-Reviewed Medical Research Program ( W81XWH1810099 and W81XWH2110198 ). Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. Nikon A1RMPsi-STORM4.0 multiphoton/super-resolution imaging system was acquired by the MBI, Office of Research, College of Medicine, and an NIH Shared Instrumentation Grant (1S10OD020026). Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = aug,
day = "6",
doi = "10.1016/j.bbr.2021.113381",
language = "English",
volume = "411",
journal = "Behavioural Brain Research",
issn = "0166-4328",
}