Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1

Nature. 2017 Mar 23;543(7646):507-512. doi: 10.1038/nature21678. Epub 2017 Mar 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / genetics*
  • Autistic Disorder / physiopathology
  • Autistic Disorder / psychology
  • Cell Nucleus / metabolism
  • Down-Regulation*
  • Female
  • Glutamic Acid / metabolism
  • Male
  • Mice
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Protein Precursors / biosynthesis
  • Protein Precursors / deficiency*
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • RNA, Messenger / metabolism
  • Seizures / psychology*
  • Social Behavior*
  • Synaptic Transmission
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ventral Tegmental Area / metabolism*


  • Cbln1 protein, mouse
  • Nerve Tissue Proteins
  • Protein Precursors
  • RNA, Messenger
  • Glutamic Acid
  • Ube3a protein, mouse
  • Ubiquitin-Protein Ligases