Hippocampal TERT Regulates Spatial Memory Formation through Modulation of Neural Development

Qi Gang Zhou; Meng Ying Liu; Han Woong Lee; Fuyuki Ishikawa; Sushil Devkota; Xin Ru Shen; Xin Jin; Hai Yin Wu; Zhigang Liu; Xiao Liu; Xun Jin; Hai Hui Zhou; Eun Jeoung Ro; Jing Zhang; Yu Zhang; Yu Hui Lin; Hoonkyo Suh; Dong Ya Zhu

doi:10.1016/j.stemcr.2017.06.014

Hippocampal TERT Regulates Spatial Memory Formation through Modulation of Neural Development

Qi Gang Zhou, Meng Ying Liu, Han Woong Lee, Fuyuki Ishikawa, Sushil Devkota, Xin Ru Shen, Xin Jin, Hai Yin Wu, Zhigang Liu, Xiao Liu, Xun Jin, Hai Hui Zhou, Eun Jeoung Ro, Jing Zhang, Yu Zhang, Yu Hui Lin, Hoonkyo Suh, Dong Ya Zhu

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

Abstract

The molecular mechanism of memory formation remains a mystery. Here, we show that TERT, the catalytic subunit of telomerase, gene knockout (Tert^−/−) causes extremely poor ability in spatial memory formation. Knockdown of TERT in the dentate gyrus of adult hippocampus impairs spatial memory processes, while overexpression facilitates it. We find that TERT plays a critical role in neural development including dendritic development and neuritogenesis of hippocampal newborn neurons. A monosynaptic pseudotyped rabies virus retrograde tracing method shows that TERT is required for neural circuit integration of hippocampal newborn neurons. Interestingly, TERT regulated neural development and spatial memory formation in a reverse transcription activity-independent manner. Using X-ray irradiation, we find that hippocampal newborn neurons mediate the modulation of spatial memory processes by TERT. These observations reveal an important function of TERT through a non-canonical pathway and encourage the development of a TERT-based strategy to treat neurological disease-associated memory impairment.

Original language	English
Pages (from-to)	543-556
Number of pages	14
Journal	Stem Cell Reports
Volume	9
Issue number	2
DOIs	https://doi.org/10.1016/j.stemcr.2017.06.014
Publication status	Published - 2017 Aug 8

Bibliographical note

Funding Information:
We thank Edward Callaway of the Salk Institute for Biological Studies for providing the pseudotyped rabies virus construction system. The authors would like to thank Chun-Xia Luo and Lei Chang for cell culture advice. This work was supported by grants from the National Natural Science Foundation of China (91232304, 31530091, 81370033, 81571269, 81572891), the National Key Research and Development Program of China (2016YFC1306703), and the Natural Science Foundation of Jiangsu Province (BK2011029, BK20140964, BK20140366), by the Key Lab of Cardiovascular and Cerebrovascular Drugs of Jiangsu Province, and by the Collaborative Innovation Center For Cardiovascular Disease Translational Medicine for data collection, analysis, and interpretation. This study was also supported by the National Institute on Alcohol Abuse and Alcoholism (R01AA022377), the Whitehall Foundation (to H.S), and the American Federation for Aging Research (to H.S.)

Publisher Copyright:
© 2017 The Authors

All Science Journal Classification (ASJC) codes

Biochemistry
Genetics
Developmental Biology
Cell Biology

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10.1016/j.stemcr.2017.06.014

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Zhou, Q. G., Liu, M. Y., Lee, H. W., Ishikawa, F., Devkota, S., Shen, X. R., Jin, X., Wu, H. Y., Liu, Z., Liu, X., Jin, X., Zhou, H. H., Ro, E. J., Zhang, J., Zhang, Y., Lin, Y. H., Suh, H., & Zhu, D. Y. (2017). Hippocampal TERT Regulates Spatial Memory Formation through Modulation of Neural Development. Stem Cell Reports, 9(2), 543-556. https://doi.org/10.1016/j.stemcr.2017.06.014

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title = "Hippocampal TERT Regulates Spatial Memory Formation through Modulation of Neural Development",

abstract = "The molecular mechanism of memory formation remains a mystery. Here, we show that TERT, the catalytic subunit of telomerase, gene knockout (Tert−/−) causes extremely poor ability in spatial memory formation. Knockdown of TERT in the dentate gyrus of adult hippocampus impairs spatial memory processes, while overexpression facilitates it. We find that TERT plays a critical role in neural development including dendritic development and neuritogenesis of hippocampal newborn neurons. A monosynaptic pseudotyped rabies virus retrograde tracing method shows that TERT is required for neural circuit integration of hippocampal newborn neurons. Interestingly, TERT regulated neural development and spatial memory formation in a reverse transcription activity-independent manner. Using X-ray irradiation, we find that hippocampal newborn neurons mediate the modulation of spatial memory processes by TERT. These observations reveal an important function of TERT through a non-canonical pathway and encourage the development of a TERT-based strategy to treat neurological disease-associated memory impairment.",

author = "Zhou, {Qi Gang} and Liu, {Meng Ying} and Lee, {Han Woong} and Fuyuki Ishikawa and Sushil Devkota and Shen, {Xin Ru} and Xin Jin and Wu, {Hai Yin} and Zhigang Liu and Xiao Liu and Xun Jin and Zhou, {Hai Hui} and Ro, {Eun Jeoung} and Jing Zhang and Yu Zhang and Lin, {Yu Hui} and Hoonkyo Suh and Zhu, {Dong Ya}",

note = "Funding Information: We thank Edward Callaway of the Salk Institute for Biological Studies for providing the pseudotyped rabies virus construction system. The authors would like to thank Chun-Xia Luo and Lei Chang for cell culture advice. This work was supported by grants from the National Natural Science Foundation of China (91232304, 31530091, 81370033, 81571269, 81572891), the National Key Research and Development Program of China (2016YFC1306703), and the Natural Science Foundation of Jiangsu Province (BK2011029, BK20140964, BK20140366), by the Key Lab of Cardiovascular and Cerebrovascular Drugs of Jiangsu Province, and by the Collaborative Innovation Center For Cardiovascular Disease Translational Medicine for data collection, analysis, and interpretation. This study was also supported by the National Institute on Alcohol Abuse and Alcoholism (R01AA022377), the Whitehall Foundation (to H.S), and the American Federation for Aging Research (to H.S.) Publisher Copyright: {\textcopyright} 2017 The Authors",

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AU - Zhou, Qi Gang

AU - Liu, Meng Ying

AU - Lee, Han Woong

AU - Ishikawa, Fuyuki

AU - Devkota, Sushil

AU - Shen, Xin Ru

AU - Jin, Xin

AU - Wu, Hai Yin

AU - Liu, Zhigang

AU - Liu, Xiao

AU - Jin, Xun

AU - Zhou, Hai Hui

AU - Ro, Eun Jeoung

AU - Zhang, Jing

AU - Zhang, Yu

AU - Lin, Yu Hui

AU - Suh, Hoonkyo

AU - Zhu, Dong Ya

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N2 - The molecular mechanism of memory formation remains a mystery. Here, we show that TERT, the catalytic subunit of telomerase, gene knockout (Tert−/−) causes extremely poor ability in spatial memory formation. Knockdown of TERT in the dentate gyrus of adult hippocampus impairs spatial memory processes, while overexpression facilitates it. We find that TERT plays a critical role in neural development including dendritic development and neuritogenesis of hippocampal newborn neurons. A monosynaptic pseudotyped rabies virus retrograde tracing method shows that TERT is required for neural circuit integration of hippocampal newborn neurons. Interestingly, TERT regulated neural development and spatial memory formation in a reverse transcription activity-independent manner. Using X-ray irradiation, we find that hippocampal newborn neurons mediate the modulation of spatial memory processes by TERT. These observations reveal an important function of TERT through a non-canonical pathway and encourage the development of a TERT-based strategy to treat neurological disease-associated memory impairment.

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Hippocampal TERT Regulates Spatial Memory Formation through Modulation of Neural Development

Abstract

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