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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,8,20]]},"abstract":"<jats:p>\n                    Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with\n                    <jats:italic>ASTN2<\/jats:italic>\n                    mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit\/hyperactivity disorder (ADHD), learning difficulties, and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional\n                    <jats:italic>Astn2<\/jats:italic>\n                    knockout (KO and cKO, respectively) mouse lines.\n                    <jats:italic>Astn2<\/jats:italic>\n                    KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors are also prominent in\n                    <jats:italic>Astn2<\/jats:italic>\n                    cKO animals, but they do not show altered behavior in the three-chamber test. By Golgi staining,\n                    <jats:italic>Astn2<\/jats:italic>\n                    KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of\n                    <jats:italic>Astn2<\/jats:italic>\n                    KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron\u2013glial adhesion protein. Immunohistochemistry and electron microscopy demonstrate a significant increase in Bergmann glia volume in the molecular layer of\n                    <jats:italic>Astn2<\/jats:italic>\n                    KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents in the\n                    <jats:italic>Astn2<\/jats:italic>\n                    KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2405901121","type":"journal-article","created":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T12:06:27Z","timestamp":1723809987000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Mice lacking\n                    <i>Astn2<\/i>\n                    have ASD-like behaviors and altered cerebellar circuit properties"],"prefix":"10.1073","volume":"121","author":[{"given":"Michalina","family":"Hanzel","sequence":"first","affiliation":[{"name":"Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayla","family":"Fernando","sequence":"additional","affiliation":[{"name":"Neurobiology Department, Duke University, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5585-4722","authenticated-orcid":false,"given":"Susan E.","family":"Maloney","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and the Intellectual and Developmental Disabilities Research Center, Washington University Medical School, St. Louis, MO 63130"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachi","family":"Horn","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065"},{"name":"InVitro Cell Research LLC, Englewood, NJ 07631"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiaoching","family":"Gong","sequence":"additional","affiliation":[{"name":"Helen and Robert Appel Alzheimer\u2019s Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1777-5614","authenticated-orcid":false,"given":"K\u00e4rt","family":"M\u00e4tlik","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3046-5362","authenticated-orcid":false,"given":"Jiajia","family":"Zhao","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Amalia","family":"Pasolli","sequence":"additional","affiliation":[{"name":"Electron Microscopy Resource Center, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f8ren","family":"Heissel","sequence":"additional","affiliation":[{"name":"Proteomics Resource Center, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6385-3997","authenticated-orcid":false,"given":"Joseph D.","family":"Dougherty","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and the Intellectual and Developmental Disabilities Research Center, Washington University Medical School, St. Louis, MO 63130"},{"name":"Department of Genetics, Washington University Medical School, St. Louis, MO 63130"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0360-8367","authenticated-orcid":false,"given":"Court","family":"Hull","sequence":"additional","affiliation":[{"name":"Neurobiology Department, Duke University, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9059-660X","authenticated-orcid":false,"given":"Mary E.","family":"Hatten","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,8,16]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1809382115"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.113.3.755"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0032-10.2010"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07953"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt669"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003128"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-63956-1.00011-4"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2013.09.033"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-070918-050258"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.23002"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12311-013-0462-2"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav0581"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0665-z"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12311-012-0355-9"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2007-1041"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.06085"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-017-0004-1"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11310"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.09.039"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.23661"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2013.08.031"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1515\/jom-2023-0129"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11015"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","unstructured":"J. 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Hanzel Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE254224. Deposited 8 March 2024.","DOI":"10.1101\/2024.02.18.580354"},{"key":"e_1_3_4_52_2","doi-asserted-by":"crossref","unstructured":"M. Hanzel Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties. PRIDE. http:\/\/www.ebi.ac.uk\/pride\/archive\/projects\/PXD052868. 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