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PTEN mutations have been identified in patients with autism spectrum disorders, characterized by macrocephaly, impaired social interactions and communication, repetitive behaviour, intellectual disability, and epilepsy. PTEN enzymatic activity is regulated by a cluster of phosphorylation sites at the C-terminus of the protein. Here, we focused on the role of PTEN T366 phosphorylation and generated a knock-in mouse line in which Pten T366 was substituted with alanine (PtenT366A\/T366A). We identify that phosphorylation of PTEN at T366 controls neuron size and connectivity of brain circuits involved in sensory processing. We show in behavioural tests that PtenT366\/T366A mice exhibit cognitive deficits and selective sensory impairments, with significant differences in male individuals. We identify restricted cellular overgrowth of cortical neurons in PtenT366A\/T366A brains, linked to increases in both dendritic arborization and soma size. In a combinatorial approach of anterograde and retrograde monosynaptic tracing using rabies virus, we characterize differences in connectivity to the primary somatosensory cortex of PtenT366A\/T366A brains, with imbalances in long-range cortico-cortical input to neurons. We conclude that phosphorylation of PTEN at T366 controls neuron size and connectivity of brain circuits involved in sensory processing and propose that PTEN T366 signalling may account for a subset of autism-related functions of PTEN.<\/jats:p>","DOI":"10.1093\/brain\/awac188","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T06:39:56Z","timestamp":1653287996000},"page":"3608-3621","source":"Crossref","is-referenced-by-count":5,"title":["The impact of phosphorylated PTEN at threonine 366 on cortical connectivity and behaviour"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5458-6287","authenticated-orcid":false,"given":"Julia M T","family":"Ledderose","sequence":"first","affiliation":[{"name":"Institute for Biochemistry, Charit\u00e9 Universit\u00e4tsmedizin Berlin , Berlin , Germany"},{"name":"Department of Biology, Humboldt Universit\u00e4t zu Berlin , 10117 Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge A","family":"Benitez","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , San Diego, CA 92121 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J","family":"Roberts","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute, Animal Models Core , La Jolla, CA 92037 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Reed","sequence":"additional","affiliation":[{"name":"Department of Medicine, Ludwig Cancer Institute , San Diego , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem","family":"Bintig","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, Charit\u00e9 Universit\u00e4tsmedizin Berlin , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew E","family":"Larkum","sequence":"additional","affiliation":[{"name":"Department of Biology, Humboldt Universit\u00e4t zu Berlin , 10117 Berlin , Germany"},{"name":"Neurocure Center for Excellence, Charit\u00e9 Universit\u00e4tsmedizin Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert N S","family":"Sachdev","sequence":"additional","affiliation":[{"name":"Department of Biology, Humboldt Universit\u00e4t zu Berlin , 10117 Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1909-4361","authenticated-orcid":false,"given":"Frank","family":"Furnari","sequence":"additional","affiliation":[{"name":"Department of Medicine, Ludwig Cancer Institute , San Diego , USA"},{"name":"Department of Medicine, University of California San Diego , La Jolla , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7873-8687","authenticated-orcid":false,"given":"Britta J","family":"Eickholt","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, Charit\u00e9 Universit\u00e4tsmedizin Berlin , Berlin , Germany"},{"name":"Neurocure Center for Excellence, Charit\u00e9 Universit\u00e4tsmedizin Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,23]]},"reference":[{"key":"2023060106303295200_awac188-B1","first-page":"2124","article-title":"TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta","volume":"57","author":"Li","year":"1997","journal-title":"Cancer Res"},{"key":"2023060106303295200_awac188-B2","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1126\/science.275.5308.1943","article-title":"PTEN, a putative 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