Objective Autism is a severe neurodevelopmental disorder characterized by problems in communication, social skills, and repetitive behavior.Abnormal immune responses have been suggested to be associated with autism.Cytokines including IL-6, IL-8, IL-12, IL-1β, TNF-α, IFN-γ, TGF-β1 and MCP-1 were reported to be increased in the blood, brain, or cerebrospinal fluid of autistic subjects.Elevated IL-6 is the most consistent finding in autism.However, the mechanisms of how IL-6 being involved in the pathogenesis of autism are poorly understood.Methods A mouse model of stably over-expressing IL-6 in brain was developed by injecting adenovirus encoding GFP IL-6 fusion protein into the cerebral lateral ventricles of P0.5 mice.A set of behavior tests was carried out to investigate the behavior in IL-6-over-expressed mice.The expression of synaptic vesicle proteins was tested using the fluorescence staining.The DiI labeling was used to outline dendritic spines in pyramidal neurons.The synaptic function was measured with extracellular field excitatory post-synaptic potentials recordings in CA1 area of the hippocampus in acute slices.Results We showed for the first time that elevation of IL-6 in the mouse brain produced certain autistic features, including impaired cognitive abilities, deficits in learning, abnormal anxiety-like traits and habituation, as well as decreased social interactions in older mice.To investigate how IL-6 elevation leads to the development of autistic phenotype, we detected that an IL-6 elevation resulted in increased excitatory synaptic formations and a decreased number of inhibitory synapses.IL-6 elevation produced an increase in the length of dendritic spines and also stimulated the formation of mushroom-shaped dendritic spines.In addition, we demonstrated that IL-6 elevation reduced postexcitatory inhibition in the mouse hippocampus.Conclusion An abnormal elevation of IL-6 in the brain could lead to the development of autism phenotype through its impairments in synaptic plasticity and neural circuitry stability.