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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / metabolism
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Excitatory Postsynaptic Potentials
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Hippocampus / metabolism
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Humans
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Long-Term Potentiation / physiology
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Long-Term Synaptic Depression
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Male
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Memory / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neuronal Plasticity / physiology*
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Neurons / enzymology
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Neurons / metabolism
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Neurons / physiology
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Synapses / metabolism
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Synapses / physiology
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Ubiquitin Thiolesterase / genetics
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Ubiquitin Thiolesterase / metabolism*
Substances
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Receptors, N-Methyl-D-Aspartate
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USP6 protein, human
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Ubiquitin Thiolesterase
Grants and funding
This work was partially supported by the National Natural Science Foundation of China (31871077, 81822014, 81571176 to XW; 81701349 to Hongfeng Z.; 81701130 to QZ; and 81471160 to HS), the National Key R&D Program of China (2016YFC1305900 to XW and HS), the Natural Science Foundation of Fujian Province of China (2017J06021 to XW), the Fundamental Research Funds for the Chinese Central Universities (20720150061 to XW and 20720180040 to ZS), Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University (SKLCSB2019KF012 to QZ), and China Postdoctoral Science Foundation (2017M612130 to QZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.