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Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability

Molecular Psychiatry volume 29, pages 1569–1582 (2024)Cite this article

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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 SNX27R196W (equivalent to human R198W) knock-in mice and found that they displayed deficits in synaptic function and learning behaviors. SNX27R196W 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 SNX27R196W 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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Fig. 1: SNX27R196W mice display deficits in learning behaviors and synaptic function.
Fig. 2: The SNX27R196W mutation induces metabolic reprogramming in astrocytes.
Fig. 3: Lactate supplementation rescues synaptic and cognitive defects in SNX27R196W mice.
Fig. 4: The SNX27R198W mutation disrupts the subcellular localization of SNX27.
Fig. 5: The SNX27R196W mutation reduces astrocytic glucose uptake and lactate secretion.
Fig. 6: A ketogenic diet restores learning and memory in SNX27R196W mice.

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Data availability

All data needed to evaluate the conclusions in the paper are presented in the paper and/or the Supplementary Materials. The RNA-seq data have been deposited into the CNGB Sequence Archive (CNSA) of the China National GeneBank DataBase (CNGBdb) with the accession number CNP0002632.

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Acknowledgements

We thank Wanjin Hong for providing the Snx27 knockout mice and SNX27 antibody, Sheng-Cai Lin for helpful discussion, and Luming Yao and Cixiong Zhang for technical assistance in TEM analysis and metabolite analysis. We also thank Novogene Co., Ltd. for technical assistance in transcriptomic analysis.

Funding

This work was supported by the National Key R&D Program of China (2021ZD0202402 to XW and HX; 2021YFA1101401 to XW), the National Natural Science Foundation of China (81822014, U21A20358 and 31871077 to XW; 81701130 to QZ; 92049202 and 92149303 to HX), the Natural Science Foundation of Fujian Province of China (2021J02004 and 2017J06021 to XW), Guangdong Basic and Applied Basic Research Foundation (2021B1515120081 to XW).

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  1. These authors contributed equally: Haibin Zhang, Qiuyang Zheng, Tiantian Guo, Shijun Zhang.

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neurosurgery, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China

    Haibin Zhang, Qiuyang Zheng, Tiantian Guo, Shuang Zheng, Ruimin Wang, Qingfang Deng, Guowei Yang, Shuo Zhang, Linxin Tang, Qiuping Qi, Lin Zhu, Hong Luo, Xian Zhang, Hao Sun, Yue Gao, Hongfeng Zhang, Huaxi Xu & Xin Wang

  2. Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong, 518057, China

    Haibin Zhang, Qiuyang Zheng & Xin Wang

  3. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China

    Shijun Zhang, Aidong Han & Chen-Song Zhang

  4. Department of Pediatrics, Xiang’an Hospital of Xiamen University, Xiamen, Fujian, 361102, China

    Xiu-Fang Zhang

  5. Department of Translational Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China

    Ying Zhou

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  1. Haibin Zhang
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Contributions

XW, QZ, and HZ designed the study and wrote the manuscript. HZ, QZ, TG, YZ, and XW performed the data analyses. SZ and AH performed the molecular dynamics simulation analyses. HZ, QZ, GY, SZ, X-FZ, XZ, and HL performed the biochemical experiments. HZ, QZ, TG, LT, and QQ performed morphological analyses. HZ, TG, and HZ performed behavioral analyses. SZ, RW, QD, LZ, YG, and HS performed LTP recording. HX and C-SZ discussed and edited the manuscript. XW supervised the project. All authors read and approved the manuscript.

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Correspondence to Xin Wang.

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Zhang, H., Zheng, Q., Guo, T. et al. Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability. Mol Psychiatry 29, 1569–1582 (2024). https://doi.org/10.1038/s41380-022-01521-x

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