Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1

Vaishnav Krishnan, David C. Stoppel, Yi Nong, Mark A. Johnson, Monica J. S. Nadler, Ekim Ozkaynak, Brian L. Teng, Ikue Nagakura, Fahim Mohammad, Michael A. Silva, Sally Peterson, Tristan J. Cruz, Ekkehard M. Kasper, Ramy Arnaout and Matthew P. Anderson ()
Additional contact information
Vaishnav Krishnan: Beth Israel Deaconess Medical Center
David C. Stoppel: Beth Israel Deaconess Medical Center
Yi Nong: Beth Israel Deaconess Medical Center
Mark A. Johnson: Beth Israel Deaconess Medical Center
Monica J. S. Nadler: Beth Israel Deaconess Medical Center
Ekim Ozkaynak: Beth Israel Deaconess Medical Center
Brian L. Teng: Beth Israel Deaconess Medical Center
Ikue Nagakura: Beth Israel Deaconess Medical Center
Fahim Mohammad: Beth Israel Deaconess Medical Center
Michael A. Silva: Beth Israel Deaconess Medical Center
Sally Peterson: Beth Israel Deaconess Medical Center
Tristan J. Cruz: Beth Israel Deaconess Medical Center
Ekkehard M. Kasper: Beth Israel Deaconess Medical Center
Ramy Arnaout: Beth Israel Deaconess Medical Center
Matthew P. Anderson: Beth Israel Deaconess Medical Center

Nature, 2017, vol. 543, issue 7646, 507-512

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature21678

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