<p>Growing preclinical and clinical evidence suggests that propofol has the potential for abuse and addiction. Clinical studies have investigated the association of propofol exposure with health, behavioral, and cognitive problems. Toll-like receptor 3 (TLR3) is a group of pattern recognition receptors in the innate immune system involved in the pathogenesis of psychiatric and neurological disorders, including neurodegeneration and drug abuse. However, whether TLR3 can be activated under propofol abuse conditions and contribute to the development of cognitive dysfunction has not been determined. Here, we demonstrated that propofol-induced attenuation of cognitive function and increased TLR3 expression in the hippocampus significantly enhanced neuroinflammation and impaired synapse formation in the hippocampus, ultimately leading to cognitive dysfunction. Mechanistically, the regulatory effects of TLR3 in propofol addiction were mediated by TLR3-mediated TRIF signaling. We further developed a propofol addiction model in TLR3 knockout mice and found that cognitive dysfunction and neuroinflammation were significantly reduced in TLR3 knockout mice. Thus, our results indicated that TLR3 contributes to propofol-induced cognitive impairment by enhancing neuroinflammation and impairing neuronal morphology in the hippocampus and might serve as a promising therapeutic target for the treatment of cognitive dysfunction caused by propofol abuse.</p>