Activation of Type I Interferon and Complement component 3a receptor signaling mediates chronic stress-induced social behavior deficits

Inflammation is involved in the pathophysiology of many neuropsychiatric disorders. Chronic stress increases inflammation and alters protective immune responses. Type I interferons (IFN-I) are key players in the peripheral inflammatory response and are implicated in mood and behavior. In the present study, we investigated the roles of neuroinflammation and synapse loss in IFN-I signaling-mediated social behavior deficits under chronic stress conditions. Our findings show that chronic unpredictable stress (CUS) induces significant increases in serum IFNβ levels. Also, CUS induced microglial activation and synapse loss in the PFC of mice. Peripheral blockade of IFN-I signaling attenuated CUS-induced neuroimmune alterations and social behavioral deficits. Furthermore, complement component 3a receptor 1 (C3ar1) mediates systemic IFNβ-induced neuroinflammation and social behavior deficits. Together, these findings identify a key role of C3ar1 in IFN-I-mediated social behavior deficits under chronic stress conditions.