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Most affected children also have recurrent seizures (epilepsy). No existing therapies are capable of comprehensively treating the deficits in AS; hence, there is an urgent need to identify new treatments. Here we show that insulin\u2010like growth factor 2 (IGF\u20102) and mannose\u20106\u2010phosphate (M6P), ligands of two independent binding sites of the cation\u2010independent M6P\/IGF\u20102 receptor (CIM6P\/IGF\u20102R), reverse most major deficits of AS modeled in mice. Subcutaneous injection of IGF\u20102 or M6P in mice modeling AS restored cognitive impairments as assessed by measurements of contextual and recognition memories, motor deficits assessed by rotarod and hindlimb clasping, and working memory\/flexibility measured by Y\u2010maze. IGF\u20102 also corrected deficits in marble burying and significantly attenuated acoustically induced seizures. An observational battery of tests confirmed that neither ligand changed basic functions including physical characteristics, general behavioral responses, and sensory reflexes, indicating that they are relatively safe. Our data provide strong preclinical evidence that targeting CIM6P\/IGF\u20102R is a promising approach for developing novel therapeutics for AS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Lay Summary<\/jats:title><jats:p>There is no effective treatment for the neurodevelopmental disorder Angelman syndrome (AS). Using a validated AS mouse model, the <jats:italic>Ube3a<\/jats:italic><jats:sup>m\u2212\/p+<\/jats:sup>, in this study we show that systemic administration of ligands of the cation independent mannose\u20106\u2010phosphate receptor, also known as insulin\u2010like growth factor 2 receptor (CIM6P\/IGF\u20102R) reverses cognitive impairment, motor deficits, as well as seizures associated with AS. Thus, ligands that activate the CIM6P\/IGF\u20102R may represent novel, potential therapeutic targets for AS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/aur.2418","type":"journal-article","created":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T14:31:09Z","timestamp":1603809069000},"page":"29-45","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["<scp>CIM6P<\/scp>\/<scp>IGF<\/scp>\u20102 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice"],"prefix":"10.1002","volume":"14","author":[{"given":"Emmanuel","family":"Cruz","sequence":"first","affiliation":[{"name":"Center for Neural Science New York University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3734-394X","authenticated-orcid":false,"given":"Giannina","family":"Descalzi","sequence":"additional","affiliation":[{"name":"Center for Neural Science New York University  New York 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