Anti-depression effects of ketogenic diet are mediated via the restoration of microglial activation and neuronal excitability in the lateral habenula - PubMed (original) (raw)

doi: 10.1016/j.bbi.2020.05.032. Epub 2020 May 12.

Guo-Bin Huang 1, Min-Dong Xu 1, Feng Gao 1, Song Lin 2, Jie Huang 1, Jin Wang 1, Yuan-Quan Li 1, Cui-Hong Wu 1, Shan Yao 1, Ying Wang 1, Yun-Long Zhang 1, Jian-Peng Teoh 3, Aiguo Xuan 4, Xiang-Dong Sun 5

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Anti-depression effects of ketogenic diet are mediated via the restoration of microglial activation and neuronal excitability in the lateral habenula

Yan-Fei Guan et al. Brain Behav Immun. 2020 Aug.

Abstract

Depression is a severe neuropsychiatric disorder, of which the underlying pathological mechanisms remain unclear. The ketogenic diet (KD) has been reported to exhibit preventative effects on depressive-like behaviors in rodents. However, the therapeutic effects of KD on depressive-like behaviors have not been illustrated thus far. Here, we found that KD treatment dramatically ameliorated depressive-like behaviors in both repeated social defeat stress (R-SDS) and lipopolysaccharide (LPS) models, indicating the potential therapeutic effects of KD on depression. Our electrophysiological studies further showed that neuronal excitability was increased in the lateral habenula (LHb) of mice exposed to R-SDS or LPS, which can be reversed in the presence of KD treatment. Moreover, R-SDS and LPS were also found to induce robust microglial inflammatory activation in the LHb. Importantly, these phenotypes were rescued in mice fed with KD. In addition, we found that the protein level of innate immune receptor Trem2 in the LHb was significantly decreased in depression models. Specific knockdown of Trem2 in LHb microglia induced depressive-like behaviors, increased neuronal excitability as well as robust microglial inflammatory activation. Altogether, we demonstrated the therapeutic effects of KD on depressive-like behaviors, which are probably mediated via the restoration of microglial inflammatory activation and neuronal excitability. Besides, we also proposed an unrecognized function of Trem2 in the LHb for depression. Our study sheds light on the pathogenesis of depression and thereby offers a potential therapeutic intervention.

Keywords: Depression; Ketogenic diet; Lateral habenula; Microglial activation; Neuronal excitability; Trem2.

Copyright © 2020. Published by Elsevier Inc.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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