{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:06:57Z","timestamp":1788048417918,"version":"build-2784847793"},"reference-count":67,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2021,6,26]],"date-time":"2021-06-26T00:00:00Z","timestamp":1624665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Acetylcholine\u2010mediated transmission plays a central role in the impairment of corticostriatal synaptic activity and plasticity in multiple DYT1 mouse models. However, the nature of such alteration remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>The aim of the present work was to characterize the mechanistic basis of cholinergic dysfunction in DYT1 dystonia to identify potential targets for pharmacological intervention.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We utilized electrophysiology recordings, immunohistochemistry, enzymatic activity assays, and Western blotting techniques to analyze in detail the cholinergic machinery in the dorsal striatum of the Tor1a<jats:sup>+\/\u2212<\/jats:sup> mouse model of DYT1 dystonia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found a significant increase in the vesicular acetylcholine transporter (VAChT) protein level, the protein responsible for loading acetylcholine (ACh) from the cytosol into synaptic vesicles, which indicates an altered cholinergic tone. Accordingly, in Tor1a<jats:sup>+\/\u2212<\/jats:sup> mice we measured a robust elevation in basal ACh content coupled to a compensatory enhancement of acetylcholinesterase (AChE) enzymatic activity. Moreover, pharmacological activation of dopamine D2 receptors, which is expected to reduce ACh levels, caused an abnormal elevation in its content, as compared to controls. Patch\u2010clamp recordings revealed a reduced effect of AChE inhibitors on cholinergic interneuron excitability, whereas muscarinic autoreceptor function was preserved. Finally, we tested the hypothesis that blockade of VAChT could restore corticostriatal long\u2010term synaptic plasticity deficits. Vesamicol, a selective VAChT inhibitor, rescued a normal expression of synaptic plasticity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Overall, our findings indicate that VAChT is a key player in the alterations of striatal plasticity and a novel target to normalize cholinergic dysfunction observed in DYT1 dystonia. \u00a9 2021 The Authors. <jats:italic>Movement Disorders<\/jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.28698","type":"journal-article","created":{"date-parts":[[2021,6,26]],"date-time":"2021-06-26T06:23:50Z","timestamp":1624688630000},"page":"2768-2779","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in <scp>DYT1<\/scp> Dystonia"],"prefix":"10.1002","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9643-2446","authenticated-orcid":false,"given":"Annalisa","family":"Tassone","sequence":"first","affiliation":[{"name":"Laboratory of Neurophysiology and Plasticity IRCCS Fondazione Santa Lucia  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8927-7107","authenticated-orcid":false,"given":"Giuseppina","family":"Martella","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology and Plasticity IRCCS Fondazione Santa Lucia  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Meringolo","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology and Plasticity IRCCS Fondazione Santa Lucia  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Vanni","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology and Plasticity IRCCS Fondazione Santa Lucia  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Sciamanna","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology and Plasticity IRCCS Fondazione Santa Lucia  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Ponterio","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology and Plasticity IRCCS Fondazione Santa Lucia  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Imbriani","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology and Plasticity IRCCS Fondazione Santa Lucia  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5940-9028","authenticated-orcid":false,"given":"Paola","family":"Bonsi","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology and Plasticity IRCCS Fondazione Santa Lucia  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8432-594X","authenticated-orcid":false,"given":"Antonio","family":"Pisani","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioral Sciences University of Pavia  Pavia Italy"},{"name":"IRCCS Mondino Foundation  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,26]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"1","article-title":"Definition of dystonia and classification of the dystonic states","volume":"14","author":"Fahn S","year":"1976","journal-title":"Adv Neurol"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0997-40"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.285"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2016.06.017"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3109\/10409238.2015.1091804"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2016.01.001"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.03.007"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(06)70574-9"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104526"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2007.07.008"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2015.02.002"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2017.06.005"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.06.017"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0041-12.2012"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0701327"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(96)00761-3"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2155-04.2004"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2006.07.006"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201809283"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awp194"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2014.01.016"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.03.024"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2011.10.002"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.11.012"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26009"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.11.010"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2020.108728"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-381328-2.00020-1"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurol.2018.07.003"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.33331"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27212"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.04.015"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.07.005"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.12.010"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14105"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn2052"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2969"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024261"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/189123a0"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1941.sp003913"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1678-08.2008"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-23274-9_10"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.06.021"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.15074"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3185"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001194"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2012.05.047"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20121662"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.08.005"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2013.01.008"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(84)90165-9"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.10-02-00508.1990"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.12.053"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2021.105342"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0407-19.2019"},{"issue":"1","key":"e_1_2_9_58_1","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/S0022-3565(25)10616-2","article-title":"Ligand binding properties of muscarinic acetylcholine receptor subtypes (m1\u2010m5) expressed in baculovirus\u2010infected insect cells","volume":"274","author":"Dong GZ","year":"1995","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(199911)46:5<761::AID-ANA12>3.0.CO;2-Z"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.08352"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104638"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20225"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-016-0362-z"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.5334\/tohm.514"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.2174\/156802610793176846"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25430"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa465"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10527"}],"container-title":["Movement Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.28698","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mds.28698","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.28698","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T14:03:14Z","timestamp":1760968994000},"score":1,"resource":{"primary":{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/10.1002\/mds.28698"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,26]]},"references-count":67,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10.1002\/mds.28698"],"URL":"https:\/\/doi.org\/10.1002\/mds.28698","archive":["Portico"],"relation":{},"ISSN":["0885-3185","1531-8257"],"issn-type":[{"value":"0885-3185","type":"print"},{"value":"1531-8257","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,26]]},"assertion":[{"value":"2020-11-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}