Author: ["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","Matthew P. Anderson"]
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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. Increasing expression of the autism-associated gene Ube3a, either alone or in combination with seizures, not only impairs sociability in mice but also reduces expression of the synaptic organizer Cbln1 in the ventral tegmental area, thus weakening glutamatergic transmission. Duplications of a region on chromosome 15 (15q11–13) result in a clinical developmental syndrome that sometimes includes autism. Patients with this syndrome carry extra copies of the gene UBE3A inherited from their mothers, which is expressed in several regions of the brain. Matthew Anderson and colleagues now show that, in mice, increases in levels of the Ube3a protein suppress sociable behaviour, and that this suppression is linked to down-regulation of Cbln1 in the ventral tegmental area, a region of the brain that is implicated in the processing of reward and aversion. Seizures, which often occur in some individuals with autism, exacerbate the decrease in sociability mediated through this pathway. The authors found that reinstating Cbln1 expression in this circuit was sufficient to restore sociability in mice with excess Ube3a and seizures.Cite this article
Krishnan, V., Stoppel, D., Nong, Y. et al. Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1. Nature 543, 507–512 (2017). https://doi.org/10.1038/nature21678 