Topoisomerase 3β knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity

Yuyoung Joo, Yutong Xue, Yue Wang, Ross A. McDevitt, Nirnath Sah, Simone Bossi, Shuaikun Su, Seung Kyu Lee, Wei Peng, Aoji Xie, Yongqing Zhang, Yi Ding, Wai Lim Ku, Soumita Ghosh, Kenneth Fishbein, Weiping Shen, Richard Spencer, Kevin Becker, Keji Zhao, Mark P. Mattson, Henriette Praag, Alexei Sharov () and Weidong Wang ()
Additional contact information
Yuyoung Joo: National Institute on Aging, National Institutes of Health
Yutong Xue: National Institute on Aging, National Institutes of Health
Yue Wang: National Institute on Aging, National Institutes of Health
Ross A. McDevitt: National Institute on Aging, National Institutes of Health
Nirnath Sah: National Institute on Aging, National Institutes of Health
Simone Bossi: National Institute on Aging, National Institutes of Health
Shuaikun Su: National Institute on Aging, National Institutes of Health
Seung Kyu Lee: National Institute on Aging, National Institutes of Health
Wei Peng: National Institute on Aging, National Institutes of Health
Aoji Xie: National Institute on Aging, National Institutes of Health
Yongqing Zhang: National Institute on Aging, National Institutes of Health
Yi Ding: Lung, and Blood Institute, National Institutes of Health
Wai Lim Ku: Lung, and Blood Institute, National Institutes of Health
Soumita Ghosh: National Institute on Aging, National Institutes of Health
Kenneth Fishbein: National Institute on Aging, National Institutes of Health
Weiping Shen: National Institute on Aging, National Institutes of Health
Richard Spencer: National Institute on Aging, National Institutes of Health
Kevin Becker: National Institute on Aging, National Institutes of Health
Keji Zhao: Lung, and Blood Institute, National Institutes of Health
Mark P. Mattson: National Institute on Aging, National Institutes of Health
Henriette Praag: National Institute on Aging, National Institutes of Health
Alexei Sharov: National Institute on Aging, National Institutes of Health
Weidong Wang: National Institute on Aging, National Institutes of Health

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Topoisomerase 3β (Top3β) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3β mutations have been linked to schizophrenia, autism, epilepsy, and cognitive impairment. Here we show that Top3β knockout mice exhibit behavioural phenotypes related to psychiatric disorders and cognitive impairment. The mice also display impairments in hippocampal neurogenesis and synaptic plasticity. Notably, the brains of the mutant mice exhibit impaired global neuronal activity-dependent transcription in response to fear conditioning stress, and the affected genes include many with known neuronal functions. Our data suggest that Top3β is essential for normal brain function, and that defective neuronal activity-dependent transcription may be a mechanism by which Top3β deletion causes cognitive impairment and psychiatric disorders.

Date: 2020
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DOI: 10.1038/s41467-020-16884-4

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