Abstract
Serotonin (5-hydroxytryptamine, 5-HT) and brain-derived neurotrophic factor (BDNF) are two signaling molecules that have important regulatory roles in the development and plasticity of neural circuits that are known to be altered in depression. However, the mechanism by which 5-HT regulates BDNF signaling is unknown. In the present study, we found that 5-HT treatment increases BDNF receptor, TrkB (tropomyosin related kinase B), levels in mouse primary cortical neurons via a Rac1 (RAS-related C3 botulinum toxin substrate 1)-dependent mechanism. Significant increases in the levels of type-2 transglutaminase (TG2, which is implicated in transamidation of 5-HT to Rac1) are observed in the mouse prefrontal cortex (PFC) following chronic exposure to stress. We also found that TG2 levels are increased in the post-mortem PFC of depressed suicide subjects relative to matched controls. Moreover, in mice, neuronal overexpression of TG2 resulted in the atrophy of neurons and reduced levels of TrkB in the PFC as well as a depressive-like phenotype. Overexpression of TG2 in mouse cortical neurons reduced TrkB levels as a result of impaired endocytosis of TrkB. TG2 inhibition by either a viral particle or pharmacological approach attenuated behavioral deficits caused by chronic unpredictable stress. Moreover, the overexpression of TrkB in the mouse PFC ameliorated the depressive-like phenotype of TG2-overexpressed mice. Taken together, these post-mortem and preclinical findings identify TG2 as a critical mediator of the altered TrkB expression and depressive-like behaviors associated with chronic exposure to stress and suggest that TG2 may represent a novel therapeutic target in depression.
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Acknowledgements
We thank Dr Chao (New York University School of Medicine) for the phospho-TrkB antibody. We would also like to acknowledge Quebec Suicide Brain Bank for post-mortem tissue samples, Mark H Tuszynski (University of California, San Diego) for the TrkB and control vectors, Edmond R Hollis (University of California, San Diego) for his helpful comments on the lentiviral experiments, Janusz Tucholski (University of Alabama) for TG2 mice, Vanderbilt KC/VBI Neurochemistry Core Lab (Vanderbilt University) for high-performance liquid chromatography analysis and Augusta University Small Animal Behavior core for the behavior experiments. This research was supported by US National Institute of Mental Health Grant R01 MH 097060 (to AP).
Author contributions
AP contributed to study design, data collection, analysis and writing. CDP contributed to data collection, analysis and writing. AC, DP and AK contributed to data collection. NH and SK contributed to lentiviral experiments. AOA contributed to statistical analysis. GT provided the human post-mortem tissues. AT and CMH contributed to the animal behavior experiments.
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Pandya, C., Hoda, N., Crider, A. et al. Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice. Mol Psychiatry 22, 745–753 (2017). https://doi.org/10.1038/mp.2016.145
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DOI: https://doi.org/10.1038/mp.2016.145
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