{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T18:44:15Z","timestamp":1770749055749,"version":"3.50.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontierspartnerships.org"],"crossmark-restriction":true},"short-container-title":["Dystonia"],"abstract":"<jats:p>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 (<jats:italic>\u0394GAG<\/jats:italic>) in <jats:italic>DYT1\/TOR1A,<\/jats:italic> coding for torsinA. <jats:italic>Dyt1<\/jats:italic> heterozygous \u0394GAG knock-in (KI) mice or global KI mice show motor deficits and abnormal Purkinje cell firing. However, Purkinje cell-specific heterozygous \u0394GAG 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.<\/jats:p>","DOI":"10.3389\/dyst.2025.14148","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T10:34:19Z","timestamp":1738146859000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 \u0394GAG knock-in mice"],"prefix":"10.3389","volume":"4","author":[{"given":"Hong","family":"Xing","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pallavi","family":"Girdhar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuning","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumiaki","family":"Yokoi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David E.","family":"Vaillancourt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1002\/mds.25475","article-title":"Phenomenology and classification of dystonia: a consensus update","volume":"28","author":"Albanese","year":"2013","journal-title":"Mov Disord"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1746","DOI":"10.1212\/wnl.54.9.1746","article-title":"The DYT1 phenotype and guidelines for diagnostic testing","volume":"54","author":"Bressman","year":"2000","journal-title":"Neurology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1097\/00019052-200208000-00014","article-title":"Dystonia: clinical features, genetics, and treatment","volume":"15","author":"Klein","year":"2002","journal-title":"Curr Opin Neurol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1136\/jnnp.2008.148270","article-title":"Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1)","volume":"79","author":"Zirn","year":"2008","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1016\/j.parkreldis.2015.08.001","article-title":"Phenotype of non-c.907_909delGAG mutations in TOR1A: DYT1 dystonia revisited","volume":"21","author":"Dobricic","year":"2015","journal-title":"Parkinsonism Relat Disord"},{"key":"B6","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1136\/jmg.2009.072082","article-title":"Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia","volume":"47","author":"Calakos","year":"2010","journal-title":"J Med Genet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1002\/mds.25921","article-title":"Combined occurrence of a novel TOR1A and a THAP1 mutation in primary dystonia","volume":"29","author":"Cheng","year":"2014","journal-title":"Mov Disord"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1002\/humu.22604","article-title":"Unraveling cellular phenotypes of novel TorsinA\/TOR1A mutations","volume":"35","author":"Vulinovic","year":"2014","journal-title":"Hum Mutat"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1002\/mds.22632","article-title":"Screening for dystonia genes DYT1, 11 and 16 in patients with writer's cramp","volume":"24","author":"Ritz","year":"2009","journal-title":"Mov Disord"},{"key":"B10","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/s100480100111","article-title":"Novel mutation in the TOR1A (DYT1) gene in atypical early onset dystonia and polymorphisms in dystonia and early onset parkinsonism","volume":"3","author":"Leung","year":"2001","journal-title":"Neurogenetics"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e358","DOI":"10.1212\/NXG.0000000000000358","article-title":"Epidemiology of DYT1 dystonia: estimating prevalence via genetic ascertainment","volume":"5","author":"Park","year":"2019","journal-title":"Neurol Genet"},{"key":"B12","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1002\/mds.25583","article-title":"Engineering animal models of dystonia","volume":"28","author":"Oleas","year":"2013","journal-title":"Mov Disord"},{"key":"B13","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.pneurobio.2014.07.002","article-title":"Genetic animal models of dystonia: common features and diversities","volume":"121","author":"Richter","year":"2014","journal-title":"Prog Neurobiol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/B978-0-12-381328-2.00020-1","article-title":"Experimental models of dystonia","volume":"98","author":"Tassone","year":"2011","journal-title":"Int Rev Neurobiol"},{"key":"B15","first-page":"67","article-title":"Mouse models of torsinA dysfunction","volume":"94","author":"Dauer","year":"2004","journal-title":"Adv Neurol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/bs.irn.2023.05.004","article-title":"Physiology of dystonia: animal studies","volume":"169","author":"Rey Hipolito","year":"2023","journal-title":"Int Rev Neurobiol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2310","DOI":"10.2174\/1570159X21666230718100156","article-title":"Synaptic dysfunction in dystonia: update from experimental models","volume":"21","author":"El Atiallah","year":"2023","journal-title":"Curr Neuropharmacol"},{"key":"B18","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/B978-0-12-405195-9.00028-7","volume-title":"Movement disorders: genetics and models","author":"Oleas","year":"2015"},{"key":"B19","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1016\/j.neuron.2005.11.010","article-title":"Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope","volume":"48","author":"Goodchild","year":"2005","journal-title":"Neuron"},{"key":"B20","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1016\/j.expneurol.2005.08.025","article-title":"Generation and characterization of Dyt1 DeltaGAG knock-in mouse as a model for early-onset dystonia","volume":"196","author":"Dang","year":"2005","journal-title":"Exp Neurol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1002\/mds.26677","article-title":"Electromyographic evidence in support of a knock-in mouse model of DYT1 Dystonia","volume":"31","author":"DeAndrade","year":"2016","journal-title":"Mov Disord"},{"key":"B22","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.nbd.2012.05.009","article-title":"Functional analysis of dopaminergic systems in a DYT1 knock-in mouse model of dystonia","volume":"48","author":"Song","year":"2012","journal-title":"Neurobiol Dis"},{"key":"B23","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/j.bbr.2016.10.028","article-title":"Sensorimotor tests unmask a phenotype in the DYT1 knock-in mouse model of dystonia","volume":"317","author":"Richter","year":"2017","journal-title":"Behav Brain Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"6459","DOI":"10.1093\/hmg\/ddv355","article-title":"A novel conditional knock-in approach defines molecular and circuit effects of the DYT1 dystonia mutation","volume":"24","author":"Weisheit","year":"2015","journal-title":"Hum Mol Genet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1002\/gene.20062","article-title":"Highly restricted expression of Cre recombinase in cerebellar Purkinje cells","volume":"40","author":"Zhang","year":"2004","journal-title":"Genesis"},{"key":"B26","doi-asserted-by":"publisher","first-page":"114471","DOI":"10.1016\/j.expneurol.2023.114471","article-title":"Cell-specific Dyt1 \u2206GAG knock-in to basal ganglia and cerebellum reveal differential effects on motor behavior and sensorimotor network function","volume":"367","author":"Wilkes","year":"2023","journal-title":"Exp Neurol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/B978-0-444-64189-2.00017-2","article-title":"The cerebellum and dystonia","volume":"155","author":"Bologna","year":"2018","journal-title":"Handb Clin Neurol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1136\/jnnp-2017-316250","article-title":"Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin?","volume":"89","author":"Kaji","year":"2018","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"B29","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1007\/s12311-016-0825-6","article-title":"Current opinions and areas of consensus on the role of the cerebellum in dystonia","volume":"16","author":"Shakkottai","year":"2017","journal-title":"Cerebellum"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1002\/mds.27123","article-title":"It's not just the basal ganglia: cerebellum as a target for dystonia therapeutics","volume":"32","author":"Tewari","year":"2017","journal-title":"Mov Disord"},{"key":"B31","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s40673-017-0064-8","article-title":"Cerebellum: an explanation for dystonia?","volume":"4","author":"Bologna","year":"2017","journal-title":"Cerebellum Ataxias"},{"key":"B32","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.neuroscience.2013.11.062","article-title":"Dystonia as a network disorder: what is the role of the cerebellum?","volume":"260","author":"Prudente","year":"2014","journal-title":"Neuroscience"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1016\/j.clinph.2013.01.003","article-title":"Dystonia and the cerebellum: a new field of interest in movement disorders?","volume":"124","author":"Filip","year":"2013","journal-title":"Clin Neurophysiol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.clinph.2011.04.027","article-title":"The cerebellum in dystonia - help or hindrance?","volume":"123","author":"Sadnicka","year":"2012","journal-title":"Clin Neurophysiol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.nbd.2010.11.006","article-title":"Animal models of dystonia: lessons from a mutant rat","volume":"42","author":"LeDoux","year":"2011","journal-title":"Neurobiol Dis"},{"key":"B36","first-page":"63","article-title":"Abnormal cerebellar output in the genetically dystonic rat","volume":"78","author":"LeDoux","year":"1998","journal-title":"Adv Neurol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"776","DOI":"10.3390\/life11080776","article-title":"Dystonia and cerebellum: from bench to bedside","volume":"11","author":"Morigaki","year":"2021","journal-title":"Life (Basel)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e22775","DOI":"10.7554\/eLife.22775","article-title":"A role for cerebellum in the hereditary dystonia DYT1","volume":"6","author":"Fremont","year":"2017","journal-title":"Elife"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e18357","DOI":"10.1371\/journal.pone.0018357","article-title":"Altered dendritic morphology of Purkinje cells in Dyt1 \u0394GAG knock-in and purkinje cell-specific Dyt1 conditional knockout mice","volume":"6","author":"Zhang","year":"2011","journal-title":"PLoS One"},{"key":"B40","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1016\/j.nbd.2013.10.003","article-title":"Subtle microstructural changes of the cerebellum in a knock-in mouse model of DYT1 dystonia","volume":"62","author":"Song","year":"2014","journal-title":"Neurobiol Dis"},{"key":"B41","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.brainresbull.2020.09.011","article-title":"The abnormal firing of Purkinje cells in the knockin mouse model of DYT1 dystonia","volume":"165","author":"Liu","year":"2020","journal-title":"Brain Res Bull"},{"key":"B42","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1038\/s41583-020-0313-3","article-title":"Reproducibility of animal research in light of biological variation","volume":"21","author":"Voelkl","year":"2020","journal-title":"Nat Rev Neurosci"},{"key":"B43","doi-asserted-by":"publisher","first-page":"103756","DOI":"10.1016\/j.mcn.2022.103756","article-title":"Hyperactivity of Purkinje cell and motor deficits in C9orf72 knockout mice","volume":"121","author":"Liu","year":"2022","journal-title":"Mol Cell Neurosci"},{"key":"B44","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.neuroscience.2020.05.021","article-title":"The role of BTBD9 in the cerebellum, sleep-like behaviors and the restless legs syndrome","volume":"440","author":"Lyu","year":"2020","journal-title":"Neuroscience"},{"key":"B45","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.neuroscience.2022.10.008","article-title":"Further studies on the role of BTBD9 in the cerebellum, sleep-like behaviors and the restless legs syndrome","volume":"505","author":"Lyu","year":"2022","journal-title":"Neuroscience"},{"key":"B46","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1093\/jb\/mvq078","article-title":"Earlier onset of motor deficits in mice with double mutations in Dyt1 and Sgce","volume":"148","author":"Yokoi","year":"2010","journal-title":"J Biochem"},{"key":"B47","doi-asserted-by":"publisher","first-page":"31458","DOI":"10.1074\/jbc.M114.589937","article-title":"p75 regulates Purkinje cell firing by modulating SK channel activity through Rac1","volume":"289","author":"Tian","year":"2014","journal-title":"J Biol Chem"},{"key":"B48","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.bbr.2011.10.024","article-title":"Abnormal nuclear envelope in the cerebellar Purkinje cells and impaired motor learning in DYT11 myoclonus-dystonia mouse models","volume":"227","author":"Yokoi","year":"2012","journal-title":"Behav Brain Res"},{"key":"B49","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1093\/hmg\/ddr528","article-title":"Abnormal nuclear envelopes in the striatum and motor deficits in DYT11 myoclonus-dystonia mouse models","volume":"21","author":"Yokoi","year":"2012","journal-title":"Hum Mol Genet"},{"key":"B50","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1038\/nrn2337","article-title":"The pathophysiological basis of dystonias","volume":"9","author":"Breakefield","year":"2008","journal-title":"Nat Rev Neurosci"},{"key":"B51","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.nbd.2019.03.007","article-title":"Advances in molecular and cell biology of dystonia: focus on torsinA","volume":"127","author":"Gonzalez-Alegre","year":"2019","journal-title":"Neurobiol Dis"},{"key":"B52","doi-asserted-by":"publisher","first-page":"114221","DOI":"10.1016\/j.bbr.2022.114221","article-title":"Motor deficit and lack of overt dystonia in Dlx conditional Dyt1 knockout mice","volume":"439","author":"Berryman","year":"2023","journal-title":"Behav Brain Res"},{"key":"B53","doi-asserted-by":"publisher","first-page":"113381","DOI":"10.1016\/j.bbr.2021.113381","article-title":"Characterization of the direct pathway in Dyt1 \u0394GAG heterozygous knock-in mice and dopamine receptor 1-expressing-cell-specific Dyt1 conditional knockout mice","volume":"411","author":"Yokoi","year":"2021","journal-title":"Behav Brain Res"},{"key":"B54","doi-asserted-by":"publisher","first-page":"104638","DOI":"10.1016\/j.nbd.2019.104638","article-title":"Decreased number of striatal cholinergic interneurons and motor deficits in dopamine receptor 2-expressing-cell-specific Dyt1 conditional knockout mice","volume":"134","author":"Yokoi","year":"2020","journal-title":"Neurobiol Dis"},{"key":"B55","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.nbd.2012.04.015","article-title":"Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA","volume":"47","author":"Sciamanna","year":"2012","journal-title":"Neurobiol Dis"},{"key":"B56","doi-asserted-by":"publisher","first-page":"e24539","DOI":"10.1371\/journal.pone.0024539","article-title":"Motor deficits and decreased striatal dopamine receptor 2 binding activity in the striatum-specific Dyt1 conditional knockout mice","volume":"6","author":"Yokoi","year":"2011","journal-title":"Plos One"},{"key":"B57","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1093\/jb\/mvm191","article-title":"Motor deficits and hyperactivity in cerebral cortex-specific Dyt1 conditional knockout mice","volume":"143","author":"Yokoi","year":"2008","journal-title":"J Biochem"},{"key":"B58","doi-asserted-by":"publisher","first-page":"e36691","DOI":"10.7554\/eLife.36691","article-title":"A cell autonomous torsinA requirement for cholinergic neuron survival and motor control","volume":"7","author":"Pappas","year":"2018","journal-title":"Elife"},{"key":"B59","doi-asserted-by":"publisher","first-page":"113783","DOI":"10.1016\/j.expneurol.2021.113783","article-title":"Cell-specific effects of Dyt1 knock-out on sensory processing, network-level connectivity, and motor deficits","volume":"343","author":"Wilkes","year":"2021","journal-title":"Exp Neurol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"105342","DOI":"10.1016\/j.nbd.2021.105342","article-title":"Alteration of the cholinergic system and motor deficits in cholinergic neuron-specific Dyt1 knockout mice","volume":"154","author":"Liu","year":"2021","journal-title":"Neurobiol Dis"},{"key":"B61","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.bbr.2012.02.029","article-title":"Improved motor performance in Dyt1 Delta GAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-out","volume":"230","author":"Yokoi","year":"2012","journal-title":"Behav Brain Res"},{"key":"B62","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/s41583-018-0002-7","article-title":"The basal ganglia and the cerebellum: nodes in an integrated network","volume":"19","author":"Bostan","year":"2018","journal-title":"Nat Rev Neurosci"},{"key":"B63","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.nbd.2017.06.015","article-title":"Forebrain knock-out of torsinA reduces striatal free-water and impairs whole-brain functional connectivity in a symptomatic mouse model of DYT1 dystonia","volume":"106","author":"DeSimone","year":"2017","journal-title":"Neurobiol Dis"},{"key":"B64","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/s41593-023-01560-9","article-title":"The cerebellum directly modulates the substantia nigra dopaminergic activity","volume":"27","author":"Washburn","year":"2024","journal-title":"Nat Neurosci"},{"key":"B65","doi-asserted-by":"publisher","first-page":"8406","DOI":"10.1523\/JNEUROSCI.1535-22.2022","article-title":"Cerebellar contributions to the basal ganglia influence motor coordination, reward processing, and movement vigor","volume":"42","author":"Yoshida","year":"2022","journal-title":"J Neurosci"}],"container-title":["Dystonia"],"original-title":[],"link":[{"URL":"https:\/\/www.frontierspartnerships.org\/articles\/10.3389\/dyst.2025.14148\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T10:34:23Z","timestamp":1738146863000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontierspartnerships.org\/articles\/10.3389\/dyst.2025.14148\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,29]]},"references-count":65,"alternative-id":["10.3389\/dyst.2025.14148"],"URL":"https:\/\/doi.org\/10.3389\/dyst.2025.14148","relation":{},"ISSN":["2813-2106"],"issn-type":[{"value":"2813-2106","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,29]]},"article-number":"14148"}}