The role of telomerase reverse transcriptase (TERT) has been extensively investigated in the contexts of aging and cancer. Interestingly, Tert− / − mice exhibit additional but unexpected aggressive and depressive behaviors, implying the potential involvement of TERT function in mood control. Our conditional rescue experiments revealed that the depressive and aggressive behaviors of Tert− / − mice originate from Tert deficiency in two distinct brain structures. Reactivation of Tert in the hippocampus was sufficient to normalize the depressive but not the aggressive behaviors of Tert− / − mice. Conversely, re-expression of Tert in the medial prefrontal cortex (mPFC) reversed the aggressive but not the depressive behavior of Tert− / − mice. Mechanistically, decreased serotonergic signaling and increased nitric oxide (NO) transmission in the hippocampus transduced Tert deficiency into depression as evidenced by our observation that the infusion of a pharmacological agonist for serotonin receptor 1a (5-HTR1A) and a selective antagonist for neuronal NO synthase into the hippocampus successfully normalized the depressive behavior of Tert− / − mice. In addition, increased serotonergic transmission by the 5-HTR1A agonist in the mPFC was sufficient to rescue the aggressive behavior of Tert− / − mice. Thus, our studies revealed a novel function of TERT in the pathology of depression and aggression in a brain structure-specific manner, providing direct evidence for the contribution of TERT to emotional control.
Bibliographical noteFunding Information:
We would like to thank Fuyuki Ishikawa in the Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Kyoto, Japan, for providing the Tert knockout mice. This study was supported by the National Institute of Alcohol Abuse and Alcoholism (R01AA022377 to HS), the Whitehall Foundation (to HS), and the American Federation for Aging Research (to HS). This work was also supported by grants from the National Natural Science Foundation of China (91232304 and 3153000026 to D-YZ; 81370033 and 81571269 to Q-GZ), the National Basic Research Program of China (973 Program) (2011CB504404 to D-YZ), the Natural Science Foundation of Jiangsu Province (BK2011029 to D-YZ; BK20140964 to XL) and by the Collaborative Innovation Center For Cardiovascular Disease Translational Medicine for data collection, analysis and interpretation.
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All Science Journal Classification (ASJC) codes
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Biological Psychiatry