title: Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1.
abstract: 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.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Vaishnav
authors.initials: V
authors.lastname: Krishnan
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Program in Neuroscience, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Stoppel
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Nong
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Johnson
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Monica J S
authors.initials: MJ
authors.lastname: Nadler
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Ekim
authors.initials: E
authors.lastname: Ozkaynak
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Teng
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Ikue
authors.initials: I
authors.lastname: Nagakura
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Fahim
authors.initials: F
authors.lastname: Mohammad
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silva
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Peterson
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Cruz
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Ekkehard M
authors.initials: EM
authors.lastname: Kasper
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Division of Clinical Informatics, Department of Internal Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Ramy
authors.initials: R
authors.lastname: Arnaout
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.|Program in Neuroscience, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.|Boston Children's Hospital Intellectual and Developmental Disabilities Research Center, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011498:Protein Precursors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012640:Seizures / Q000523:psychology*; D012919:Social Behavior; D009435:Synaptic Transmission; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000378:metabolism*
chemical_list: C092370:Cbln1 protein, mouse; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D018698:Glutamic Acid; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases