Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice

Shan Yao, Min-Dong Xu, Ying Wang, Shen-Ting Zhao, Jin Wang, Gui-Fu Chen, Wen-Bing Chen, Jian Liu, Guo-Bin Huang, Wen-Juan Sun, Yan-Yan Zhang, Huan-Li Hou, Lei Li and Xiang-Dong Sun ()
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Shan Yao: Guangzhou Medical University
Min-Dong Xu: Guangzhou Medical University
Ying Wang: Guangzhou Medical University
Shen-Ting Zhao: Guangzhou Medical University
Jin Wang: Guangxi University of Science and Technology
Gui-Fu Chen: Guangzhou Medical University
Wen-Bing Chen: Nanchang University
Jian Liu: Guangzhou Medical University
Guo-Bin Huang: Guangzhou Medical University
Wen-Juan Sun: Guangxi University of Science and Technology
Yan-Yan Zhang: Guangzhou Medical University
Huan-Li Hou: Guangzhou Medical University
Lei Li: ShanghaiTech University
Xiang-Dong Sun: Guangzhou Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Alterations in energy metabolism are associated with depression. However, the role of glycolysis in the pathogenesis of depression and the underlying molecular mechanisms remain unexplored. Through an unbiased proteomic screen coupled with biochemical verifications, we show that the levels of glycolysis and lactate dehydrogenase A (LDHA), a glycolytic enzyme that catalyzes L-lactate production, are reduced in the dorsomedial prefrontal cortex (dmPFC) of stress-susceptible mice in chronic social defeat stress (CSDS) model. Conditional knockout of LDHA from the brain promotes depressive-like behaviors in both male and female mice, accompanied with reduced L-lactate levels and decreased neuronal excitability in the dmPFC. Moreover, these phenotypes could be duplicated by knockdown of LDHA in the dmPFC or specifically in astrocytes. In contrast, overexpression of LDHA reverses these phenotypic changes in CSDS-susceptible mice. Mechanistic studies demonstrate that L-lactate promotes neuronal excitability through monocarboxylic acid transporter 2 (MCT2) and by inhibiting large-conductance Ca2+-activated potassium (BK) channel. Together, these results reveal a role of LDHA in maintaining neuronal excitability to prevent depressive-like behaviors.

Date: 2023
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DOI: 10.1038/s41467-023-36209-5

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