Sarm1, a neuronal inflammatory regulator, controls social interaction, associative memory and cognitive flexibility in mice.

Impaired neurodevelopment leads to several psychiatric disorders, including autism, schizophrenia and attention deficiency hyperactivity disorder. Our prior study showed that sterile alpha and TIR motif-containing 1 protein (Sarm1) regulates neuronal morphogenesis through at least two pathways. Sarm1 controls neuronal morphogenesis, including dendritic arborization, axonal outgrowth and establishment of neuronal polarity, through the MKK-JNK pathway. Neuronally expressed Sarm1 also regulates the expression of inflammatory cytokines in the brain, which have also been shown to impact brain development and function. Because the reduction of Sarm1 expression negatively influences neuronal development, here we investigated whether Sarm1 controls mouse behaviors. We analyzed two independent Sarm1 transgenic mouse lines using a series of behavioral assays, and found that the reduction of Sarm1 protein levels had a limited effect on locomotion and anxiety. However, Sarm1 knockdown mice exhibited impairments in cued and contextual fear conditioning as well as cognitive flexibility. Moreover, the three-chambered social test, reciprocal social interaction and social transmission of food preference further illustrated deficiencies in Sarm1 knockdown mice in social interaction. These findings suggest that Sarm1, a molecule that regulates innate immunity and neuronal morphogenesis, regulates social behaviors and cognition. We conclude that Sarm1 is involved in immune response, neural development and psychiatric disorders.