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Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability

Zhang, Haibin, Zheng, Qiuyang, Guo, Tiantian, Zhang, Shijun, Zheng, Shuang, Wang, Ruimin, Deng, Qingfang, Yang, Guowei, Zhang, Shuo, Tang, Linxin, Qi, Qiuping, Zhu, Lin, Zhang, Xiu-Fang, Luo, Hong, Zhang, Xian, Sun, Hao, Gao, Yue, Zhang, Hongfeng, Zhou, Ying, Han, Aidong, Zhang, Chen-Song, Xu, Huaxi, Wang, Xin·2024·Molecular Psychiatry
DOI 10.1038/s41380-022-01521-x
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Abstract

Astrocyte aerobic glycolysis provides vital trophic support for central nervous system neurons. However, whether and how astrocytic metabolic dysregulation contributes to neuronal dysfunction in intellectual disability (ID) remain unclear. Here, we demonstrate a causal role for an ID-associated SNX27 mutation (R198W) in cognitive deficits involving reshaping astrocytic metabolism. We generated SNX27 R196W (equivalent to human R198W) knock-in mice and found that they displayed deficits in synaptic function and learning behaviors. SNX27 R196W resulted in attenuated astrocytic glucose uptake via GLUT1, leading to reduced lactate production and a switch from homeostatic to reactive astrocytes. Importantly, lactate supplementation or a ketogenic diet restored neuronal oxidative phosphorylation and reversed cognitive deficits in SNX27 R196W mice. In summary, we illustrate a key role for astrocytic SNX27 in maintaining glucose supply and glycolysis and reveal that altered astrocytic metabolism disrupts the astrocyte-neuron interaction, which contributes to ID. Our work also suggests a feasible strategy for treating ID by restoring astrocytic metabolic function.

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Metadata

Authors
Zhang, H., Zheng, Q., Guo, T., Zhang, S., Zheng, S., Wang, R., Deng, Q., Yang, G., Zhang, S., Tang, L., Qi, Q., Zhu, L., Zhang, X.-F., Luo, H., Zhang, X., Sun, H., Gao, Y., Zhang, H., Zhou, Y., Han, A., Zhang, C.-S., Xu, H., & Wang, X.
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-03-25
Volume
29
Issue
6
Pages
1569-1582
ISSN
  • 1359-4184
  • 1476-5578
DOI
10.1038/s41380-022-01521-x
Cited by
38
References
14
Language
en
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