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  2. Brain-derived neurotrophic factor upregulates synaptic GluA1 in the amygdala to promote depression in response to psychological stress

Brain-derived neurotrophic factor upregulates synaptic GluA1 in the amygdala to promote depression in response to psychological stress

  • Biochem Pharmacol. 2021 Oct;192:114740. doi: 10.1016/j.bcp.2021.114740.
Yanning Li 1 Yitong He 2 Haoliang Fan 3 Zhuo Wang 4 Jian Huang 2 Gehua Wen 5 Xiaohan Wang 2 Qiqian Xie 2 Pingming Qiu 6
Affiliations

Affiliations

  • 1 School of Forensic Medicine, Southern Medical University, Guangzhou, PR China; Department of Forensic Medicine, School of Basic Medicine, Gannan Medical University, Ganzhou, PR China.
  • 2 School of Forensic Medicine, Southern Medical University, Guangzhou, PR China.
  • 3 School of Forensic Medicine, Southern Medical University, Guangzhou, PR China; School of Basic Medicine and Life Science, Hainan Medical University, Haikou, PR China.
  • 4 Department of Infertility and Sexual Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China.
  • 5 School of Forensic Medicine, China Medical University, Shenyang, PR China.
  • 6 School of Forensic Medicine, Southern Medical University, Guangzhou, PR China. Electronic address: qiupm@smu.edu.cn.
Abstract

Psychological stress impairs neuronal structure and function and leads to emotional disorders, but the underlying mechanisms have not yet been fully elucidated. The amygdala is closely correlated with emotional regulation. In the present study, we analyzed whether the amygdala plasticity is regulated by psychological stress and explored their regulatory mechanism. We established a mouse psychological stress model using an improved communication box, wherein mice were exposed to chronic fear and avoided physical stress interference. After the 14-day psychological stress paradigm, mice exhibited significantly increased depressive behaviors (decreased sucrose consumption in the sucrose preference test and longer immobility time in the forced swimming test). HPLC, ELISA, and molecular and morphological evidences showed that psychological stress increased the content of glutamate and the expression of glutamatergic neurons, upregulated the content of the stress hormone corticosterone, and activated the CREB/BDNF pathway in the amygdala. Furthermore, psychological stress induced an increased density of dendritic spines and LTD impairment in the amygdala. Importantly, virus-mediated silencing of BDNF in the basolateral amygdala (BLA) nuclei reversed the depression-like behaviors and the increase of synaptic GluA1 and its phosphorylation at Ser831 and Ser845 sites in psychologically stressed mice. This process was likely achieved through mTOR signaling activation. Finally, we treated primary amygdala neurons with corticosterone to mimic psychological stress; corticosterone-induced upregulation of GluA1 was prevented by BDNF and mTOR antagonists. Thus, activation of the CREB/BDNF pathway in the amygdala following psychological stress upregulates synaptic GluA1 via mTOR signaling, which dysregulates synaptic plasticity of the amygdala, eventually promoting depression.

Keywords

Amygdala; BDNF; Depression; GluA1; Psychological stress; Synaptic plasticity.

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