{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T22:53:49Z","timestamp":1779231229535,"version":"3.51.4"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T00:00:00Z","timestamp":1703116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Behav. Neurosci."],"abstract":"<jats:p>Progressive myoclonus epilepsy type 1 (EPM1) is an autosomal recessively inherited childhood\u2013adolescence onset neurodegenerative disease caused by mutations in the cystatin B (<jats:italic>CSTB<\/jats:italic> gene). The key clinical manifestation in EPM1 is progressive, stimulus-sensitive, in particular action-induced myoclonus. The cystatin B-deficient mouse model, <jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>, has been described to present with myoclonic seizures and progressive ataxia. Here we describe results from in-depth behavioral phenotyping of the <jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mouse model in pure isogenic 129S2\/SvHsd background covering ages from 1.5 to 6\u2009months. We developed a method for software-assisted detection of myoclonus from video recordings of the <jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice. Additionally, we observed that the mice were hyperactive and showed reduced startle response, problems in motor coordination and lack of inhibition. We were, however, not able to demonstrate an ataxic phenotype in them. This detailed behavioral phenotyping of the <jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice reveals new aspects of this mouse model. The nature of the motor problems in the <jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice seems to be more complex and more resembling the human phenotype than initially described.<\/jats:p>","DOI":"10.3389\/fnbeh.2023.1325051","type":"journal-article","created":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T04:16:43Z","timestamp":1703132203000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["In depth behavioral phenotyping unravels complex motor disturbances in Cstb\u2212\/\u2212 mouse, a model for progressive myoclonus epilepsy type 1"],"prefix":"10.3389","volume":"17","author":[{"given":"Eveliina","family":"Pollari","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saara","family":"Tegelberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harry","family":"Bj\u00f6rklund","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reetta","family":"K\u00e4lvi\u00e4inen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna-Elina","family":"Lehesjoki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antti","family":"Haapalinna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2596","DOI":"10.1210\/en.2018-00220","article-title":"Comparing postnatal development of gonadal hormones and associated social behaviors in rats, mice, and humans","volume":"159","author":"Bell","year":"2018","journal-title":"Endocrinology"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.nbd.2012.04.005","article-title":"Loss of cortical GABA terminals in Unverricht-Lundborg disease","volume":"47","author":"Buzzi","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"105418","DOI":"10.1016\/j.nbd.2021.105418","article-title":"Cystatin B-deficiency triggers ectopic histone H3 tail cleavage during neurogenesis","volume":"156","author":"Daura","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e11419","DOI":"10.15252\/emmm.201911419","article-title":"Cystatin B is essential for proliferation and interneuron migration in individuals with EPM 1 epilepsy","volume":"12","author":"Di Matteo","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.nbd.2006.11.006","article-title":"A pathogenetic hypothesis of Unverricht-Lundborg disease onset and progression","volume":"25","author":"Franceschetti","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1175851","DOI":"10.3389\/fnmol.2023.1175851","article-title":"Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice","volume":"16","author":"Gorski","year":"2023","journal-title":"Front. Mol. Neurosci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"570640","DOI":"10.3389\/fnmol.2020.570640","article-title":"Quantitative changes in the mitochondrial proteome of cerebellar synaptosomes from preclinical cystatin B-deficient mice","volume":"13","author":"Gorski","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1002\/neu.10253","article-title":"Cathepsin B but not cathepsins L or S contributes to the pathogenesis of Unverricht-Lundborg progressive myoclonus epilepsy (EPM1)","volume":"56","author":"Houseweart","year":"2003","journal-title":"J. Neurobiol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1111\/j.1528-1167.2007.01422.x","article-title":"Molecular background of EPM1\u2014Unverricht-Lundborg disease","volume":"49","author":"Joensuu","year":"2008","journal-title":"Epilepsia"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1371\/journal.pone.0089321","article-title":"Gene expression alterations in the cerebellum and granule neurons of Cstb\u2212\/\u2212 mouse are associated with early synaptic changes and inflammation","volume":"9","author":"Joensuu","year":"2014","journal-title":"PLoS One"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1152\/jn.00063.2018","article-title":"Abnormal motor cortical adaptation to external stimulus in Unverricht-Lundborg disease (progressive myoclonus type 1, EPM1)","volume":"120","author":"Julkunen","year":"2018","journal-title":"J. Neurophysiol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1055\/s-0035-1552620","article-title":"Progressive myoclonus epilepsies","volume":"35","author":"K\u00e4lvi\u00e4inen","year":"2015","journal-title":"Semin. Neurol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"2256","DOI":"10.2353\/ajpath.2010.100461","article-title":"Cystatin C rescues degenerating neurons in a cystatin B-knockout mouse model of progressive myoclonus epilepsy","volume":"177","author":"Kaur","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1177\/1550059416646292","article-title":"Startle response in progressive myoclonic epilepsy","volume":"48","author":"Kiziltan","year":"2017","journal-title":"Clin. EEG Neurosci."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.jneumeth.2015.12.001","article-title":"Automated quantitative analysis to assess motor function in different rat models of impaired coordination and ataxia","volume":"268","author":"Kyriakou","year":"2016","journal-title":"J.Neurosci. Methods."},{"key":"ref16","article-title":"Progressive myoclonic epilepsy type 1","volume-title":"GeneReviews\u00ae","author":"Lehesjoki","year":"2020"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1867","DOI":"10.1093\/hmg\/10.18.1867","article-title":"Cystatin B-deficient mice have increased expression of apoptosis and glial activation genes","volume":"10","author":"Lieuallen","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1212\/WNL.0000000000002422","article-title":"CSTB null mutation associated with microcephaly, early developmental delay, and severe dyskinesia","volume":"86","author":"Mancini","year":"2016","journal-title":"Neurology"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1148\/radiol.13122458","article-title":"White matter degeneration with Unverricht-Lundborg progressive myoclonus epilepsy: A translational diffusion-tensor imaging study in patients and cystatin B-deficient mice","volume":"269","author":"Manninen","year":"2013","journal-title":"Radiology"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1371\/journal.pone.0090709","article-title":"Progressive volume loss and white matter degeneration in Cstb-deficient mice: A diffusion tensor and longitudinal volumetry MRI study","volume":"9","author":"Manninen","year":"2014","journal-title":"PLoS One"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/ejhg.2017.39","article-title":"Severe neurodegeneration, progressive cerebral volume loss and diffuse hypomyelination associated with a homozygous frameshift mutation in CSTB","volume":"25","author":"O\u2019Brien","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1002\/glia.22760","article-title":"Abnormal microglial activation in the Cstb\u2212\/\u2212 mouse, a model for progressive myoclonus epilepsy, EPM1","volume":"63","author":"Okuneva","year":"2015","journal-title":"Glia"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12974-016-0764-7","article-title":"Brain inflammation is accompanied by peripheral inflammation in Cstb \u2212\/\u2212 mice, a model for progressive myoclonus epilepsy","volume":"13","author":"Okuneva","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"195","DOI":"10.3389\/fnmol.2019.00195","article-title":"Cystatin B involvement in synapse physiology of rodent brains and human cerebral organoids","volume":"12","author":"Penna","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/3059","article-title":"Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice","volume":"20","author":"Pennacchio","year":"1998","journal-title":"Nat. Genet."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1126\/science.271.5256.1731","article-title":"Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)","volume":"271","author":"Pennacchio","year":"1996","journal-title":"Science"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1006\/nbdi.2001.0450","article-title":"Assessment of sensorimotor and cognitive deficits induced by a moderate traumatic injury in the right parietal cortex of the rat","volume":"8","author":"Piot-Grosjean","year":"2001","journal-title":"Neurobiol. Dis."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"2464","DOI":"10.1016\/j.clinph.2021.06.026","article-title":"Wearable monitoring of positive and negative myoclonus in progressive myoclonic epilepsy type 1","volume":"132","author":"Rissanen","year":"2021","journal-title":"Clin. Neurophysiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"2593","DOI":"10.1111\/epi.16692","article-title":"Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy","volume":"61","author":"Sierra-Torre","year":"2020","journal-title":"Epilepsia"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1111\/epi.17466","article-title":"Short- and long-interval intracortical inhibition in EPM1 is related to genotype","volume":"64","author":"Silvennoinen","year":"2023","journal-title":"Epilepsia"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1177\/0269881105051524","article-title":"The mouse beam walking assay offers improved sensitivity over the mouse rotarod in determining motor coordination deficits induced by benzodiazepines","volume":"19","author":"Stanley","year":"2005","journal-title":"J. Psychopharmacol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1097\/NEN.0b013e31823e68e1","article-title":"Early microglial activation precedes neuronal loss in the brain of the Cstb \u2212\/\u2212 mouse model of progressive myoclonus epilepsy, EPM1","volume":"71","author":"Tegelberg","year":"2012","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/0014-5793(91)80804-C","article-title":"The cystatins: protein inhibitors of cysteine proteinases","volume":"285","author":"Turk","year":"1991","journal-title":"FEBS Lett."}],"container-title":["Frontiers in Behavioral Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2023.1325051\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T04:16:48Z","timestamp":1703132208000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2023.1325051\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,21]]},"references-count":33,"alternative-id":["10.3389\/fnbeh.2023.1325051"],"URL":"https:\/\/doi.org\/10.3389\/fnbeh.2023.1325051","relation":{},"ISSN":["1662-5153"],"issn-type":[{"value":"1662-5153","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,21]]},"article-number":"1325051"}}