TGF-β1 is an anti-inflammatory cytokine that is augmented in the brain of autistic patients and that can affect brain development. In this work, we studied the effects of overexpressing TGF-β1 in the dentate gyrus of adult or young mice on behavior. TGF-β1 overexpression during postnatal development led to a long-term decrease in social interaction and to long-term increases in self-grooming and depression-related behaviors. Our analysis shows that these behavioral changes correlate with the long-term downregulation of TGF-β1 and IL-6 expression in the dentate gyrus, as well as to decreases in the mRNA levels of the synaptic protein neuroligin 3 and in the number of Reelin-positive neurons in the dentate gyrus. In contrast, chronic expression of TGF-β1 during adulthood led to transient opposite effects on these behaviors. These results show a central role of hippocampal TGF-β1 in the programming and modulation of social interaction, repetitive behavior and depression-related behavior. Finally, our data suggest a role of hippocampal TGF-β1 and early-life neuroinflammation in the development of the behavioral alterations observed in autism spectrum disorders.

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