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.
Bibliographical noteFunding 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.)
All Science Journal Classification (ASJC) codes
- Developmental Biology
- Cell Biology