TY - JOUR T1 - Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1. AU - Krishnan,Vaishnav, AU - Stoppel,David C, AU - Nong,Yi, AU - Johnson,Mark A, AU - Nadler,Monica J S, AU - Ozkaynak,Ekim, AU - Teng,Brian L, AU - Nagakura,Ikue, AU - Mohammad,Fahim, AU - Silva,Michael A, AU - Peterson,Sally, AU - Cruz,Tristan J, AU - Kasper,Ekkehard M, AU - Arnaout,Ramy, AU - Anderson,Matthew P, Y1 - 2017/03/15/ PY - 2015/09/11/received PY - 2017/01/27/accepted PY - 2017/3/16/pubmed PY - 2017/8/5/medline PY - 2017/3/16/entrez SP - 507 EP - 512 JF - Nature JO - Nature VL - 543 IS - 7646 N2 - Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant type of autism linked to increased gene dosages of UBE3A, which encodes a ubiquitin ligase with transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus downregulates the glutamatergic synapse organizer Cbln1, which is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases in UBE3A. This Ube3a-seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA), where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activation of, or restoration of Cbln1 in, VTA glutamatergic neurons reverses the sociability deficits induced by Ube3a and/or seizures. Our results suggest that gene and seizure interactions in VTA glutamatergic neurons impair sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/28297715/Autism_gene_Ube3a_and_seizures_impair_sociability_by_repressing_VTA_Cbln1_ L2 - https://doi.org/10.1038/nature21678 DB - PRIME DP - Unbound Medicine ER -