{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T01:33:46Z","timestamp":1786325626954,"version":"build-2736575974"},"reference-count":81,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"47","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2024,11,22]]},"abstract":"<jats:p>A dynamic equilibrium between dopamine and acetylcholine (ACh) is essential for striatal circuitry and motor function, as imbalances are associated with Parkinson\u2019s disease (PD) and levodopa-induced dyskinesia (LID). Conventional theories posit that cholinergic signaling is pathologically elevated in PD as a result of increased ACh release, which contributes to motor deficits. However, using approaches to measure receptor-mediated signaling, we found that, rather than the predicted enhancement, the strength of cholinergic transmission at muscarinic M4 receptor synapses on direct pathway medium spiny neurons was decreased in dopamine-depleted mice. This adaptation was due to a reduced postsynaptic M4 receptor function, resulting from down-regulated receptors and downstream signaling. Restoring M4 transmission unexpectedly led to a partial alleviation of motor deficits and LID dyskinetic behavior, revealing an unexpected prokinetic effect in addition to the canonical antikinetic role of M4 receptors. These findings indicate that decreased M4 function differentially contributes to parkinsonian and LID pathophysiology, representing a promising target for therapeutic intervention.<\/jats:p>","DOI":"10.1126\/sciadv.adp6301","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T13:59:41Z","timestamp":1732111181000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":27,"title":["Reduced striatal M4-cholinergic signaling following dopamine loss contributes to parkinsonian and\n                    <scp>l<\/scp>\n                    -DOPA\u2013induced dyskinetic behaviors"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9927-3639","authenticated-orcid":true,"given":"Beatriz E.","family":"Nielsen","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA."},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4175-2933","authenticated-orcid":true,"given":"Christopher P.","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA."},{"name":"Aligning Science Across Parkinson\u2019s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-061010-113641"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.03.004"},{"key":"e_1_3_2_4_2","first-page":"802","article-title":"The pathogenesis of Parkinson\u2019s disease: A new hypothesis","volume":"87","author":"Barbeau A.","year":"1962","unstructured":"A. Barbeau, The pathogenesis of Parkinson\u2019s disease: A new hypothesis. Can. Med. Assoc. J. 87, 802\u2013807 (1962).","journal-title":"Can. Med. Assoc. J."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1961.03040360001001"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(93)91459-6"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1447-0594.2010.00588.x"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111034"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.09.034"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0873-16.2016"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.06.014"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8023166"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.56920"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1700"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02247477"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(90)90807-L"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(89)90631-6"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.06.013"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6345-10.2011"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(76)93095-6"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.14-05-03351.1994"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.11-10-03218.1991"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.06.021"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27740"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.08.017"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3843-09.2010"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.12.008"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.11.029"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(02)01910-6"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.10.039"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196902132800701"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.11.053"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605208103"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.15-01-00458.1995"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1840-08.2008"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.09.028"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/syn.22287"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2017.08.016"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2022.114011"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.69.1.795"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80117-8"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.052"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(03)00447-7"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.11.015"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0953-816X.2004.03336.x"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3154-18.2019"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2009.08.041"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1214696110"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2017.06.008"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2011.00071"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.01.017"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1040"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.05.059"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-018-1847-7"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471142301.ns0925s41"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27372"},{"key":"e_1_3_2_57_2","first-page":"CD003735","article-title":"Anticholinergics for symptomatic management of Parkinson\u2019s disease","volume":"2003","author":"Katzenschlager R.","year":"2002","unstructured":"R. Katzenschlager, C. Sampaio, J. Costa, A. Lees, Anticholinergics for symptomatic management of Parkinson\u2019s disease. Cochrane Database Syst. Rev. 2003, CD003735 (2002).","journal-title":"Cochrane Database Syst. Rev."},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.1999.00788.x"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2015.06.005"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2018.00065"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-23-10237.1999"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1006\/mcne.2001.1083"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.11.5035"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(02)01004-2"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.8056"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2003.01610.x"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-019-0099-z"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.22049"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00377-X"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcab109"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1002\/mdc3.13319"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn0532"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44903"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0220-20.2020"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.0c00162"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2021.05.026"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105044"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.5b00063"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2014.06.013"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.121.261939"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05995-9"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1763-19.2019"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.adp6301","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T14:13:31Z","timestamp":1732284811000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adp6301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,22]]},"references-count":81,"journal-issue":{"issue":"47","published-print":{"date-parts":[[2024,11,22]]}},"alternative-id":["10.1126\/sciadv.adp6301"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.adp6301","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.08.23.554510","asserted-by":"object"}]},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,22]]},"assertion":[{"value":"2024-04-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadp6301"}}