{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T23:31:07Z","timestamp":1786318267420,"version":"build-2736575974"},"posted":{"date-parts":[[2024,8,28]]},"group-title":"Neuroscience","reference-count":42,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T00:00:00Z","timestamp":1724803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Loss-of-function mutations in\n                  <jats:italic>GNAL<\/jats:italic>\n                  have been linked to an adult-onset, isolated dystonia that is largely indistinguishable from idiopathic dystonia.\n                  <jats:italic>GNAL<\/jats:italic>\n                  encodes G\u03b1\n                  <jats:sub>olf<\/jats:sub>\n                  , a heterotrimeric G-protein \u03b1 subunit with a defined molecular function to increase the production of the second messenger cAMP. G\u03b1\n                  <jats:sub>olf<\/jats:sub>\n                  is abundant in the striatum, and is the only stimulatory G-protein in many cell types of the striatum. Due to the defined molecular signaling pathway and expression pattern of G\u03b1\n                  <jats:sub>olf<\/jats:sub>\n                  , the clear genetic link to dystonia makes\n                  <jats:italic>GNAL<\/jats:italic>\n                  an exciting target to understand the pathological mechanisms of not only this genetic dystonia, but also the larger idiopathic disease. To better understand\n                  <jats:italic>GNAL<\/jats:italic>\n                  -linked dystonia, we generated a novel genetic mouse model that allows us to conditionally knock out\n                  <jats:italic>Gnal<\/jats:italic>\n                  in a site and time-specific manner. In the current study we used genetic or AAV based approaches to express Cre to knockout striatal\n                  <jats:italic>Gnal<\/jats:italic>\n                  in our novel\n                  <jats:italic>Gnal fl\/fl<\/jats:italic>\n                  model. We then performed motor behavioral testing and\n                  <jats:italic>ex vivo<\/jats:italic>\n                  whole-cell patch clamp electrophysiology of striatal spiny projection neurons to interrogate how loss of\n                  <jats:italic>Gnal<\/jats:italic>\n                  leads to dystonia. Mice with conditional striatal knockout of\n                  <jats:italic>Gnal<\/jats:italic>\n                  show hindlimb clasping, other dystonia-like postures, less motor coordination, slowness, and torticollis as compared to age-matched controls. Furthermore, striatal spiny projection neurons show increased excitability in\n                  <jats:italic>Gnal<\/jats:italic>\n                  knockout animals. These exciting data are the first to report uninduced, overt dystonia in a mouse model of\n                  <jats:italic>GNAL-<\/jats:italic>\n                  linked dystonia, and directly correlate these with changes in spiny projection neuron electrophysiological properties. Our results show that adult loss of\n                  <jats:italic>Gnal<\/jats:italic>\n                  in the striatum leads to the development of dystonia, through homeostatic, paradoxical increases in spiny projection neuron excitability, and suggest that therapeutic strategies aimed at decreasing this hyperexcitable phenotype may provide symptomatic relief for patients with disease.\n                <\/jats:p>\n                <jats:p>\n                  <jats:bold>One Sentence Summary:<\/jats:bold>\n                  When\n                  <jats:italic>Gnal<\/jats:italic>\n                  is knocked out in the striatum of mice we observe overt behavioral symptoms and hyperexcitability in striatal spiny projection neurons.\n                <\/jats:p>","DOI":"10.1101\/2024.08.26.609754","type":"posted-content","created":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T11:05:16Z","timestamp":1724843116000},"source":"Crossref","is-referenced-by-count":3,"title":["Conditional Knockout of Striatal Gnal Produces Dystonia-like Motor Phenotypes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2727-3327","authenticated-orcid":false,"given":"Nicole E.","family":"Chambers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Barsoum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Curry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"Kaplan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Garan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Gallardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick","family":"Staab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Nabert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Hutchinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Millett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8023-1313","authenticated-orcid":false,"given":"Mark S.","family":"Moehle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024083104250649000_2024.08.26.609754v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2337"},{"key":"2024083104250649000_2024.08.26.609754v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2496"},{"key":"2024083104250649000_2024.08.26.609754v1.3","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/j.parkreldis.2015.08.026","article-title":"Mutations in GNAL gene in 214 cases with isolated dystonia","volume":"21","year":"2015","journal-title":"Parkinsonism & related disorders"},{"key":"2024083104250649000_2024.08.26.609754v1.4","first-page":"e78","article-title":"Homozygous GNAL mutation associated with familial childhood-onset generalized dystonia. 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