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Regulation of glutamate transporter 1 via BDNF-TrkB signaling plays a role in the anti-apoptotic and antidepressant effects of ketamine in chronic unpredictable stress model of depression

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Abstract

Rationale

Growing evidence suggests that downregulated clearance of glutamate and signaling pathways involving brain-derived neurotrophic factor (BDNF) and its receptor TrkB play a role in morphological changes in the hippocampus of depressed patients. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is the most attractive antidepressant, although precise mechanisms are unknown.

Objective

In this study, we examined whether hippocampal BDNF-TrkB signaling underlies the antidepressant effects of ketamine via upregulating glutamate transporter 1 (GLT-1) in rats, subjected to the chronic unpredictable stress (CUS) for 42 days. The rats received a single injection of ketamine (10 mg/kg, i.p.) and/or a TrkB inhibitor, K252a (1 μl, 2 mM, intracerebroventicular (i.c.v.)) on day 43. Behavioral tests and brain sample collection were evaluated 24 h later.

Results

The CUS-exposed rats exhibited depression- and anxiety-like behaviors; decreased number of glial fibrillary acidic protein (GFAP)-positive (but not NeuN-positive) cells in the dentate gyrus (DG), CA1, and CA3 areas; increased number of cleaved caspase-3-positive astrocytes; reduced spine density; lower ratio of Bcl2 to Bax; and decreased levels of BDNF, phosphorylated cAMP response element binging protein (CREB), GLT-1, and postsynaptic density 95 (PSD95) proteins in the hippocampus. Ketamine alleviated the CUS-induced abnormalities. The effects of ketamine were antagonized by pretreatment with K252a.

Conclusions

Our findings suggest that regulation of GLT-1 on astrocytes, responsible for 90 % of glutamate reuptake from the synapse, through BDNF-TrkB signaling is involved in mediation of the therapeutic effects of ketamine on behavioral abnormalities and morphological changes in the hippocampus of the CUS-exposed rats.

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Acknowledgments

This study was supported by a grant from the National Natural Science Foundation of China (Nos. 81271216 and 81471105) and a Grant-in-Aid from the Minister of Education, Culture, Sports, Science, and Technology of Japan (to K.H., No. 24116006).

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Authors and Affiliations

  1. Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China

    Wen-Xue Liu, Jing Wang, Ze-Min Xie, Ning Xu, Guang-Fen Zhang, Min Jia, Zhi-Qiang Zhou & Jian-Jun Yang

  2. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China

    Ze-Min Xie, Ning Xu & Jian-Jun Yang

  3. Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, China

    Ze-Min Xie, Ning Xu & Jian-Jun Yang

  4. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan

    Kenji Hashimoto

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  1. Wen-Xue Liu
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Correspondence to Kenji Hashimoto or Jian-Jun Yang.

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Liu, WX., Wang, J., Xie, ZM. et al. Regulation of glutamate transporter 1 via BDNF-TrkB signaling plays a role in the anti-apoptotic and antidepressant effects of ketamine in chronic unpredictable stress model of depression. Psychopharmacology 233, 405–415 (2016). https://doi.org/10.1007/s00213-015-4128-2

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