Abstract
Microglial cells are known to contribute to brain development and behaviors, but the mechanisms behind such functions are not fully understood. Here, we show that mice deficient in inflammasome regulators, including caspase-1 (Casp1), NLR family pyrin domain containing 3 (Nlrp3), IL-1 receptor (Il-1r), and gasdermin D (Gsdmd), exhibit behavior abnormalities characterized by hyperactivity and low anxiety levels. Furthermore, we found that expression of Casp1 in CX3CR1+ myeloid cells, which includes microglia, is required for preventing these abnormal behaviors. Through tissue clearing and 3D imaging, we discovered that small numbers of Cx3cr1-GFP+ fetal microglial cells formed clusters and underwent lytic cell death in the primitive thalamus and striatum between embryonic day (E)12.5 and E14.5. This lytic cell death was diminished in Casp1-deficient mice. Further analysis of the microglial clusters showed the presence of Pax6+ neural progenitor cells (NPCs); thus, we hypothesized that microglial lytic cell death is important for proper neuronal development. Indeed, increased numbers of neurons were observed in the thalamic subset in adult Casp1−/− brains. Finally, injection of drug inhibitors of NLRP3 and CASP1 into wild-type (WT) pregnant mice from E12.5 to E14.5, the period when lytic cell death was detected, was sufficient to induce atypical behaviors in offspring. Taken together, our data suggests that the inflammasome cascade in microglia is important for regulating neuronal development and normal behaviors, and that genetic or pharmacological inhibition of this pathway can induce atypical behaviors in mice.
Highlights
Normal brain development is a series of complex events that can be affected by either genetic or environmental factors
We have shown that the NLRP3-CASP1GSDMD/IL-1b cascade in microglia is required for normal brain development and prevents behavior abnormalities such as hyperactivity and low anxiety levels (Fig. 1)
The re-expression of Casp1 in these cells in Casp1-deficient mice restored normal behaviors (Fig. 2). These results indicate the importance of myeloid cells, microglia, in early brain development to ensure normal behaviors in mice
Summary
Normal brain development is a series of complex events that can be affected by either genetic or environmental factors. Disruptions in these events can result in neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder (ADHD), autism, and intellectual disabilities characterized by atypical behaviors. Cell death by apoptosis has been shown to be essential for normal brain development by controlling the number of neurons in the brain and by helping to establish functional circuits (Yoshida et al, 1998; Yamaguchi and Miura, 2015; Fricker et al, 2018); it has not yet been reported whether other types of cell death (lytic cell death such as pyroptosis) are important for regulating these developmental processes. The molecular mechanisms behind how microglia shape these circuits and affect their corresponding behaviors are not well understood
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