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Specifically, lysine acetylation within the ER appears to influence the efficiency of the secretory pathway by affecting ER-mediated quality control. Mutations or duplications in AT-1\/SLC33A1 have been linked to diseases such as familial spastic paraplegia, developmental delay with premature death, and autism spectrum disorder with intellectual disability. In this study, we generated an AT-1 Tg mouse model that selectively overexpresses human AT-1 in neurons. These animals demonstrate cognitive deficits, autistic-like social behavior, aberrations in synaptic plasticity, an increased number of dendritic spines and branches, and widespread proteomic changes. We also found that AT-1 activity regulates acetyl-CoA flux, causing epigenetic modulation of the histone epitope H3K27 and mitochondrial adaptation. In conclusion, our results indicate that increased expression of AT-1 can cause an autistic-like phenotype by affecting key neuronal metabolic pathways.<\/jats:p>","DOI":"10.1084\/jem.20151776","type":"journal-article","created":{"date-parts":[[2016,5,30]],"date-time":"2016-05-30T14:12:45Z","timestamp":1464617565000},"page":"1267-1284","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":40,"title":["Increased expression of AT-1\/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation"],"prefix":"10.1084","volume":"213","author":[{"given":"Rikki","family":"Hullinger","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 1"},{"name":"Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53705 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53705 2"},{"name":"School of Pharmacy and Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajing","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Dowell","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53705 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Bomba-Warczak","sequence":"additional","affiliation":[{"name":"Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53705 2"},{"name":"Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705 5"},{"name":"Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53705 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather A.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Rodent Models Core, Waisman Center, University of Wisconsin-Madison, Madison, WI 53705 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Burger","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Wisconsin-Madison, Madison, WI 53705 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin R.","family":"Chapman","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705 5"},{"name":"Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53705 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Denu","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53705 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingjun","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Puglielli","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 1"},{"name":"Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705 5"},{"name":"Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, WI 53705 9"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,5,30]]},"reference":[{"key":"2023072603412943900_bib1","doi-asserted-by":"publisher","first-page":"28623","DOI":"10.1074\/jbc.R115.657130","article-title":"The regulation of synaptic protein turnover","volume":"290","author":"Alvarez-Castelao","year":"2015","journal-title":"J. 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