Defective cell death of distinct microglial subsets contributes to ADHD-like behavior in mice

Microglia are resident immune cells in the central nervous system that play essential roles to maintain homeostasis and neuronal function. Microglia are heterogeneous cells but the mechanisms by which they contribute to normal brain development remain unclear. Here,we show that microglia in the developing striatum and thalamus undergo pyroptosis,a type of lytic cell death that occurs as a result of Caspase-1 (CASP1) activation downstream of inflammasomes. We observe that pyroptosis occurs in a spatiotemporally regulated and Casp1-dependent manner during fetal brain development. Mice lacking Casp1 or the inflammasome regulating molecules, NLRP3, IL-1R, and Gasdermin D exhibit behavior changes characterized by hyperactivity, inattention, and impulsivity that are similar to attention-deficit/hyperactivity disorder (ADHD). Furthermore, re-expression of Casp1 in Cx3cr1+ cells including microglia restores normal behavior and cell death. We demonstrate that injection of an NLRP3 inhibitor into pregnant wild-type mice is sufficient to induce ADHD-like behaviors in offspring. These data suggest that microglial inflammasome activation and pyroptosis are essential for normal brain development and that genetic and pharmacological disruptions in this pathway may represent new ADHD risk factors.