Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 ΔGAG knock-in mice
DYT1 dystonia is an inherited early-onset generalized dystonia characterized by sustained muscle contractions causing abnormal, repetitive movements or postures. Most DYT1 patients have a heterozygous trinucleotide GAG deletion (ΔGAG) in DYT1/TOR1A, coding for torsinA. Dyt1 heterozygous ΔGAG knock-i...
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Frontiers Media S.A.
2025-01-01
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| author | Hong Xing Pallavi Girdhar Yuning Liu Fumiaki Yokoi David E. Vaillancourt Yuqing Li |
| author_facet | Hong Xing Pallavi Girdhar Yuning Liu Fumiaki Yokoi David E. Vaillancourt Yuqing Li |
| author_sort | Hong Xing |
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| description | DYT1 dystonia is an inherited early-onset generalized dystonia characterized by sustained muscle contractions causing abnormal, repetitive movements or postures. Most DYT1 patients have a heterozygous trinucleotide GAG deletion (ΔGAG) in DYT1/TOR1A, coding for torsinA. Dyt1 heterozygous ΔGAG knock-in (KI) mice or global KI mice show motor deficits and abnormal Purkinje cell firing. However, Purkinje cell-specific heterozygous ΔGAG conditional KI mice (Pcp2-KI) show improved motor performance, reduced sensory-evoked brain activation in the striatum and midbrain, and reduced functional connectivity of the striatum with the anterior medulla. Whether Pcp2-KI mice show similar abnormal Purkinje cell firing as the global KI mice, suggesting a cell-autonomous effect causes the abnormal Purkinje cell firing in the global KI mice, is unknown. We used acute cerebellar slice recording in Pcp2-KI mice to address this issue. The Pcp2-KI mice exhibited no changes in spontaneous firing and intrinsic excitability compared to the control mice. While membrane properties were largely unchanged, the resting membrane potential was slightly hyperpolarized, which was associated with decreased baseline excitability. Our results suggest that the abnormal Purkinje cell firing in the global KI mice was not cell-autonomous and was caused by physiological changes elsewhere in the brain circuits. Our results also contribute to the ongoing research of how basal ganglia and cerebellum interact to influence motor control in normal states and movement disorders. |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-78eab2d336aa4667b199dbb8ef736bd52025-01-29T10:34:11ZengFrontiers Media S.A.Dystonia2813-21062025-01-01410.3389/dyst.2025.1414814148Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 ΔGAG knock-in miceHong Xing0Pallavi Girdhar1Yuning Liu2Fumiaki Yokoi3David E. Vaillancourt4Yuqing Li5Department of Neurology, Norman Fixel Institute of Neurological Diseases, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, United StatesDepartment of Neurology, Norman Fixel Institute of Neurological Diseases, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, United StatesDepartment of Neurology, Norman Fixel Institute of Neurological Diseases, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, United StatesDepartment of Neurology, Norman Fixel Institute of Neurological Diseases, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, United StatesDepartment of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, United StatesDepartment of Neurology, Norman Fixel Institute of Neurological Diseases, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, United StatesDYT1 dystonia is an inherited early-onset generalized dystonia characterized by sustained muscle contractions causing abnormal, repetitive movements or postures. Most DYT1 patients have a heterozygous trinucleotide GAG deletion (ΔGAG) in DYT1/TOR1A, coding for torsinA. Dyt1 heterozygous ΔGAG knock-in (KI) mice or global KI mice show motor deficits and abnormal Purkinje cell firing. However, Purkinje cell-specific heterozygous ΔGAG conditional KI mice (Pcp2-KI) show improved motor performance, reduced sensory-evoked brain activation in the striatum and midbrain, and reduced functional connectivity of the striatum with the anterior medulla. Whether Pcp2-KI mice show similar abnormal Purkinje cell firing as the global KI mice, suggesting a cell-autonomous effect causes the abnormal Purkinje cell firing in the global KI mice, is unknown. We used acute cerebellar slice recording in Pcp2-KI mice to address this issue. The Pcp2-KI mice exhibited no changes in spontaneous firing and intrinsic excitability compared to the control mice. While membrane properties were largely unchanged, the resting membrane potential was slightly hyperpolarized, which was associated with decreased baseline excitability. Our results suggest that the abnormal Purkinje cell firing in the global KI mice was not cell-autonomous and was caused by physiological changes elsewhere in the brain circuits. Our results also contribute to the ongoing research of how basal ganglia and cerebellum interact to influence motor control in normal states and movement disorders.https://www.frontierspartnerships.org/articles/10.3389/dyst.2025.14148/fullPurkinje cellsdystoniatorsinADYT1electrophysiology |
| spellingShingle | Hong Xing Pallavi Girdhar Yuning Liu Fumiaki Yokoi David E. Vaillancourt Yuqing Li Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 ΔGAG knock-in mice Dystonia Purkinje cells dystonia torsinA DYT1 electrophysiology |
| title | Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 ΔGAG knock-in mice |
| title_full | Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 ΔGAG knock-in mice |
| title_fullStr | Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 ΔGAG knock-in mice |
| title_full_unstemmed | Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 ΔGAG knock-in mice |
| title_short | Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 ΔGAG knock-in mice |
| title_sort | subtle changes in purkinje cell firing in purkinje cell specific dyt1 δgag knock in mice |
| topic | Purkinje cells dystonia torsinA DYT1 electrophysiology |
| url | https://www.frontierspartnerships.org/articles/10.3389/dyst.2025.14148/full |
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