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. 2025 Feb;30(2):423-434.
doi: 10.1038/s41380-024-02675-6. Epub 2024 Aug 2.

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

Ashutosh Tripathi  1 , Alona Bartosh  1 , Jocelyn Mata  1 , Chale Jacks  1 , Amit Kumar Madeshiya  1 , Usama Hussein  2   3 , L Elliot Hong  1 , Zhongming Zhao  1   2 , Anilkumar Pillai  4   5
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Microglial type I interferon signaling mediates chronic stress-induced synapse loss and social behavior deficits

Ashutosh Tripathi et al. Mol Psychiatry. 2025 Feb.

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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Conflict of interest statement

Competing interests: 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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