The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability

Fanwei Zeng, Xuehai Ma, Lin Zhu, Qiang Xu, Yuzhe Zeng, Yue Gao, Guilin Li, Tiantian Guo, Haibin Zhang, Xiaoyan Tang, Ziqiang Wang, Zesen Ye, Liangkai Zheng, Hongfeng Zhang, Qiuyang Zheng, Kunping Li, Jinfang Lu, Xueting Qi, Hong Luo, Xian Zhang, Zhanxiang Wang, Yulin Zhou, Yi Yao, Rongqin Ke, Ying Zhou, Yan Liu, Hao Sun, Timothy Huang, Zhicheng Shao, Huaxi Xu and Xin Wang

PLOS Biology, 2019, vol. 17, issue 12, 1-31

Abstract: Ubiquitin-specific protease (USP) 6 is a hominoid deubiquitinating enzyme previously implicated in intellectual disability and autism spectrum disorder. Although these findings link USP6 to higher brain function, potential roles for USP6 in cognition have not been investigated. Here, we report that USP6 is highly expressed in induced human neurons and that neuron-specific expression of USP6 enhances learning and memory in a transgenic mouse model. Similarly, USP6 expression regulates N-methyl-D-aspartate-type glutamate receptor (NMDAR)-dependent long-term potentiation and long-term depression in USP6 transgenic mouse hippocampi. Proteomic characterization of transgenic USP6 mouse cortex reveals attenuated NMDAR ubiquitination, with concomitant elevation in NMDAR expression, stability, and cell surface distribution with USP6 overexpression. USP6 positively modulates GluN1 expression in transfected cells, and USP6 down-regulation impedes focal GluN1 distribution at postsynaptic densities and impairs synaptic function in neurons derived from human embryonic stem cells. Together, these results indicate that USP6 enhances NMDAR stability to promote synaptic function and cognition.This study identifies the hominoid-specific USP6 as a novel deubiquitinase of NMDA receptors, and shows that neuronal expression of human USP6 transgene enhances cognitive and synaptic function in mice, suggesting a potential role of USP6 in the evolution of human intelligence.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pbio00:3000525

DOI: 10.1371/journal.pbio.3000525

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