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© 2019 Zeng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability
Author
Zeng, Fanwei; Ma, Xuehai; Zhu, Lin; Xu, Qiang; Zeng, Yuzhe; Gao, Yue; Li, Guilin; Guo, Tiantian; Zhang, Haibin; Tang, Xiaoyan; Wang, Ziqiang; Ye, Zesen; Zheng, Liangkai; Zhang, Hongfeng; Zheng, Qiuyang; Li, Kunping; Lu, Jinfang; Qi, Xueting; Luo, Hong; Zhang, Xian; Wang, Zhanxiang; Zhou, Yulin; Yao, Yi; Rongqin Ke; Zhou, Ying; Liu, Yan; Sun, Hao; Huang, Timothy; Shao, Zhicheng; Xu, Huaxi; Wang, Xin
First page
e3000525
Section
Research Article
Publication year
2019
Publication date
Dec 2019
Publisher
Public Library of Science
ISSN
15449173
e-ISSN
15457885
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2339846055
Copyright
© 2019 Zeng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.