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Loss of liver X receptor β in astrocytes leads to anxiety-like behaviors via regulating synaptic transmission in the medial prefrontal cortex in mice

Molecular Psychiatry volume 26, pages 6380–6393 (2021)Cite this article

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Abstract

Astrocytes are integral components of synaptic transmission, and their dysfunction leads to neuropsychiatric disorders such as anxiety and depression. Liver X receptor β (LXRβ) is expressed in astrocytes, and LXRβ global knockout mice shows impaired synaptic formation. In order to define the role of LXRβ in astrocytes, we used a conditional Cre-loxP system to specifically remove LXRβ from astrocytes. We found that this deletion caused anxiety-like but not depressive-like behaviors in adult male mice. This behavioral phenotype could be completely reproduced by selective deletion of LXRβ in astrocytes in the medial prefrontal cortex (mPFC). Pyramidal neurons in layer V of mPFC are involved in mood behaviors. We found that there was an increased spontaneous excitatory synaptic transmission in layer V pyramidal neurons of the mPFC of these mice. This was concurrent with increased dendritic complexity, despite normal appearance and number of dendritic spines. In addition, gene ontology analysis of RNA sequencing revealed that deletion of astrocytic LXRβ led to the enrichment of the process of synaptic transmission in mPFC. Finally, we also confirmed that renormalized excitatory synaptic transmission in layer V pyramidal neurons alleviated the anxiety in mice with astrocytic LXRβ deletion in mPFC. Together, our findings reveal that astrocytic LXRβ in mPFC is critical in the regulation of synaptic transmission, and this provides a potential new target for treatment of anxiety-like behavior.

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Fig. 1: Deletion of LXRβ in astrocytes induced anxiety-like behaviors in 8–12 weeks old male mice.
Fig. 2: Deletion of LXRβ in astrocytes increased vGlut1 expression in layer V of mPFC.
Fig. 3: Loss of astrocytic LXRβ enhanced excitatory synaptic transmission and increased basal dendritic complexity of layer V pyramidal neurons in mPFC.
Fig. 4: Differential expression profiling in the mPFC of LXRβ cKOGFAP and LXRβfl/fl mice.
Fig. 5: Knockdown of LXRβ in astrocytes of the adult mPFC recapitulated the anxiety-like behavior seen in the LXRβ cKOGFAP mice.

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Acknowledgements

This study was supported by the National Key R&D Program of China (2017YFE0103700), the National Nature Science Foundation of China (No. 31871043), and the Swedish Research Council and a grant from the Robert A. Welch Foundation (E-0004, J-ÅG).

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Authors and Affiliations

  1. Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, PR China

    Xin Li, Hongyu Zhong, Zhongke Wang, Rui Xiao, Tianyao Liu, Chuan Wu, Jiao Zou, Lian Wang & Xiaotang Fan

  2. Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden

    Per Antonson, Ivan Nalvarte & Jan-Ake Gustafsson

  3. Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, PR China

    Haiwei Xu

  4. Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA

    Margaret Warner & Jan-Ake Gustafsson

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Li, X., Zhong, H., Wang, Z. et al. Loss of liver X receptor β in astrocytes leads to anxiety-like behaviors via regulating synaptic transmission in the medial prefrontal cortex in mice. Mol Psychiatry 26, 6380–6393 (2021). https://doi.org/10.1038/s41380-021-01139-5

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