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Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice
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 glycol...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9911790/ https://www.ncbi.nlm.nih.gov/pubmed/36759610 http://dx.doi.org/10.1038/s41467-023-36209-5 |
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author | Yao, Shan Xu, Min-Dong Wang, Ying Zhao, Shen-Ting Wang, Jin Chen, Gui-Fu Chen, Wen-Bing Liu, Jian Huang, Guo-Bin Sun, Wen-Juan Zhang, Yan-Yan Hou, Huan-Li Li, Lei Sun, Xiang-Dong |
author_facet | Yao, Shan Xu, Min-Dong Wang, Ying Zhao, Shen-Ting Wang, Jin Chen, Gui-Fu Chen, Wen-Bing Liu, Jian Huang, Guo-Bin Sun, Wen-Juan Zhang, Yan-Yan Hou, Huan-Li Li, Lei Sun, Xiang-Dong |
author_sort | Yao, Shan |
collection | PubMed |
description | 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 Ca(2+)-activated potassium (BK) channel. Together, these results reveal a role of LDHA in maintaining neuronal excitability to prevent depressive-like behaviors. |
format | Online Article Text |
id | pubmed-9911790 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-99117902023-02-11 Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice Yao, Shan Xu, Min-Dong Wang, Ying Zhao, Shen-Ting Wang, Jin Chen, Gui-Fu Chen, Wen-Bing Liu, Jian Huang, Guo-Bin Sun, Wen-Juan Zhang, Yan-Yan Hou, Huan-Li Li, Lei Sun, Xiang-Dong Nat Commun Article 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 Ca(2+)-activated potassium (BK) channel. Together, these results reveal a role of LDHA in maintaining neuronal excitability to prevent depressive-like behaviors. Nature Publishing Group UK 2023-02-09 /pmc/articles/PMC9911790/ /pubmed/36759610 http://dx.doi.org/10.1038/s41467-023-36209-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Yao, Shan Xu, Min-Dong Wang, Ying Zhao, Shen-Ting Wang, Jin Chen, Gui-Fu Chen, Wen-Bing Liu, Jian Huang, Guo-Bin Sun, Wen-Juan Zhang, Yan-Yan Hou, Huan-Li Li, Lei Sun, Xiang-Dong Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice |
title | Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice |
title_full | Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice |
title_fullStr | Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice |
title_full_unstemmed | Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice |
title_short | Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice |
title_sort | astrocytic lactate dehydrogenase a regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9911790/ https://www.ncbi.nlm.nih.gov/pubmed/36759610 http://dx.doi.org/10.1038/s41467-023-36209-5 |
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