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Microglial type I interferon signaling mediates chronic stress-induced synapse loss and social behavior deficits

Molecular Psychiatry (2024)Cite this article

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Abstract

Inflammation and synapse loss have been associated with deficits in social behavior and are involved in pathophysiology of many neuropsychiatric disorders. Synapse loss, characterized by reduction in dendritic spines can significantly disrupt synaptic connectivity and neural circuitry underlying social behavior. Chronic stress is known to induce loss of spines and dendrites in the prefrontal cortex (PFC), a brain region implicated in social behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of type I Interferon (IFN-I) signaling in chronic unpredictable stress (CUS)-induced synapse loss and behavior deficits in mice. We found increased expression of type I IFN receptor (IFNAR) in microglia following CUS. Conditional knockout of microglial IFNAR in adult mice rescued CUS-induced social behavior deficits and synapse loss. Bulk RNA sequencing data show that microglial IFNAR deletion attenuated CUS-mediated changes in the expression of genes such as Keratin 20 (Krt20), Claudin-5 (Cldn5) and Nuclear Receptor Subfamily 4 Group A Member 1 (Nr4a1) in the PFC. Cldn5 and Nr4a1 are known for their roles in synaptic plasticity. Krt20 is an intermediate filament protein responsible for the structural integrity of epithelial cells. The reduction in Krt20 following CUS presents a novel insight into the potential contribution of cytokeratin in stress-induced alterations in neuroplasticity. Overall, these results suggest that microglial IFNAR plays a critical role in regulating synaptic plasticity and social behavior deficits associated with chronic stress conditions.

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Fig. 1: Chronic stress induces increases in serum IFNβ levels and deficits in social behavior.
Fig. 2: Chronic stress promotes neuroinflammation and reduction in synaptic density.
Fig. 3: Chronic stress induces increase in IFNAR expression in microglia.
Fig. 4: Microglial IFNAR deletion attenuates chronic stress-induced social behavior deficits and synapse loss.
Fig. 5: Microglial IFNAR deletion attenuates chronic stress-induced decreases in Krt20, Cldn5 and Nr4a1 mRNA levels in the PFC.

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Data availability

The data that support the findings of this study are available upon request from the corresponding author.

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Acknowledgements

The authors acknowledge the funding support from US National Institutes of Health (MH120876, MH121959, MH128771), and the Merit Review Award (BX004758) from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development to AP. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. AP acknowledges the funding support from Louis A Faillace Endowed Chair in Psychiatry. ZZ was partially supported by NIH grants (R01LM012806, R01LM012806-07S1, U01AG079847). The authors thank lab members of the Bioinformatics Systems Medicine Laboratory (BSML) for the valuable help. The RNA-seq data were generated by the UTHealth Cancer Genomics Core funded by Cancer Prevention and Research Institute of Texas (CPRIT RP180734). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. Usama Hussein

    Present address: Department of Lymphoma & Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Ashutosh Tripathi, Alona Bartosh, Jocelyn Mata, Chale Jacks, Amit Kumar Madeshiya, L. Elliot Hong, Zhongming Zhao & Anilkumar Pillai

  2. Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Usama Hussein & Zhongming Zhao

  3. Charlie Norwood VA Medical Center, Augusta, GA, USA

    Anilkumar Pillai

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  1. Ashutosh Tripathi
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Contributions

AT: performed the experiments, analyzed the data and prepared the initial manuscript draft. AB: performed the experiments and analyzed the data. JM: performed the experiments and analyzed the data. CJ: performed the experiments and analyzed the data. AM: performed the experiments and analyzed the data. UH: performed RNAseq analysis. ZZ: performed RNAseq analysis. LEH: participated in the data interpretation and manuscript editing. AP: designed the research and edited the manuscript. All authors had an opportunity to review and provide input on the final manuscript.

Corresponding author

Correspondence to Anilkumar Pillai.

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The authors declare no competing interests.

Ethics approval and consent to participate

The animal studies were approved (#AWC-20-0148) by the Animal Welfare Committee (AWC) of the University of Texas Health Science Center at Houston (UTHealth Houston).

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Tripathi, A., Bartosh, A., Mata, J. et al. Microglial type I interferon signaling mediates chronic stress-induced synapse loss and social behavior deficits. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02675-6

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