Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice.
Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice.
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星形胶质细胞乳酸脱氢酶 A 通过小鼠乳酸稳态调节神经元兴奋性和抑郁样行为
DOI：
10.1038/s41467-023-36209-5
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发表时间：
2023-02-09
影响因子：
16.6
通讯作者：
Sun, Xiang-Dong
中科院分区：
文献类型：
--
作者：
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
能量代谢的改变与抑郁症相关。然而，糖酵解在抑郁症发病机制中的作用以及潜在的分子机制仍未被探究。通过无偏蛋白质组学筛选结合生化验证，我们发现，在慢性社交挫败应激（CSDS）模型中，易受应激小鼠的背内侧前额叶皮质（dmPFC）中糖酵解水平以及乳酸脱氢酶A（LDHA，一种催化L -乳酸生成的糖酵解酶）水平降低。大脑中LDHA的条件性敲除促进了雄性和雌性小鼠的抑郁样行为，同时伴有dmPFC中L -乳酸水平降低和神经元兴奋性下降。此外，通过在dmPFC中或特异性在星形胶质细胞中敲低LDHA可重现这些表型。相反，在CSDS易感小鼠中过表达LDHA可逆转这些表型变化。机制研究表明，L -乳酸通过单羧酸转运蛋白2（MCT2）以及抑制大电导钙激活钾（BK）通道来促进神经元兴奋性。总之，这些结果揭示了LDHA在维持神经元兴奋性以预防抑郁样行为方面的作用。
糖酵解在抑郁症中的作用尚不清楚。在此，作者报道了在社会应激下存在糖酵解缺陷，并证明在小鼠中星形胶质细胞的LDHA通过乳酸稳态影响神经元兴奋性和抑郁样行为。
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. The role of glycolysis in depression is unclear. Here the authors report a glycolytic deficit under social stress and demonstrate that astrocytic LDHA affects neuronal excitability and depressive-like behaviours via lactate homeostasis in mice.
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影响因子：
29
作者：
Díaz-García CM;Mongeon R;Lahmann C;Koveal D;Zucker H;Yellen G
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影响因子：
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作者：
Fuenfschilling, Ursula;Supplie, Lotti M.;Mahad, Don;Boretius, Susann;Saab, Aiman S.;Edgar, Julia;Brinkmann, Bastian G.;Kassmann, Celia M.;Tzvetanova, Iva D.;Moebius, Wiebke;Diaz, Francisca;Meijer, Dies;Suter, Ueli;Hamprecht, Bernd;Sereda, Michael W.;Moraes, Carlos T.;Frahm, Jens;Goebbels, Sandra;Nave, Klaus-Armin
通讯作者：
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