Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1

 

View on Nature.com
 

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

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1.

Author information

1
Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
2
Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
3
Program in Neuroscience, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
4
Department of Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
5
Division of Clinical Informatics, Department of Internal Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
6
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
7
Boston Children's Hospital Intellectual and Developmental Disabilities Research Center, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.

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.

PMID:
 
28297715
 
PMCID:
 
PMC5364052
 [Available on 2017-09-15]
 
DOI:
 
10.1038/nature21678

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.