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自闭症基因Ube3a和癫痫发作通过抑制腹侧被盖区Cbln1来损害社交能力。

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

作者信息

Krishnan Vaishnav, Stoppel David C, Nong Yi, Johnson Mark A, Nadler Monica J S, Ozkaynak Ekim, Teng Brian L, Nagakura Ikue, Mohammad Fahim, Silva Michael A, Peterson Sally, Cruz Tristan J, Kasper Ekkehard M, Arnaout Ramy, Anderson Matthew P

机构信息

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.

出版信息

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

DOI:10.1038/nature21678
PMID:28297715
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5364052/
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.

摘要

母系遗传的15q11 - 13染色体三联体导致一种常见且高度外显的自闭症类型，其与UBE3A基因剂量增加有关，UBE3A编码一种具有转录共调节功能的泛素连接酶。在此，我们利用体内小鼠遗传学研究表明，细胞核中UBE3A增加会下调谷氨酸能突触组织者Cbln1，而Cbln1是小鼠社交能力所必需的。癫痫发作也会抑制Cbln1，并发现其会使UBE3A无症状增加的小鼠出现社交能力受损。这种Ube3a - 癫痫协同作用定位于中脑腹侧被盖区（VTA）的谷氨酸能神经元，在该区域Cbln1缺失会损害社交能力并减弱谷氨酸能传递。我们提供了临床前证据，即基于病毒载体的VTA谷氨酸能神经元的化学遗传学激活或Cbln1恢复可逆转由Ube3a和/或癫痫发作引起的社交能力缺陷。我们的结果表明，VTA谷氨酸能神经元中的基因与癫痫相互作用通过下调Cbln1来损害社交能力，Cbln1是自闭症基因不断扩展的蛋白质相互作用网络中的一个关键节点。

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