Reactivation of Tert in the medial prefrontal cortex and hippocampus rescues aggression and depression of Tert(-/-) mice.
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.
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China.
Q-G
QG
Zhou
Department of Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China.
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HY
Wu
Department of Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China.
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H
Zhou
Department of Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China.
M-Y
MY
Liu
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei Laboratory Animal Research Center, Yonsei University, Seoul, Korea.
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HW
Lee
Department of Chinese Medicine, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
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X
Liu
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei Laboratory Animal Research Center, Yonsei University, Seoul, Korea.
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S
Devkota
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
E J
EJ
Ro
Department of Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China.
D-Y
DY
Zhu
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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H
Suh
D000374:Aggression / Q000502:physiology*; D000818:Animals; D001143:Arousal / Q000502:physiology; D003433:Crosses, Genetic; D003863:Depression / Q000235:genetics* / Q000503:physiopathology; D006624:Hippocampus / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism; D017397:Prefrontal Cortex / Q000503:physiopathology*; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D014161:Transduction, Genetic
D044282:Receptor, Serotonin, 5-HT1A; D019001:Nitric Oxide Synthase; D019098:Telomerase; C509187:Tert protein, mouse