Lytic cell death in specific microglial subsets is required for preventing atypical behavior in mice

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eNeuro. 2021 Jan 4:ENEURO.0342-20.2020. doi: 10.1523/ENEURO.0342-20.2020. Online ahead of print.

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), 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 days E12.5 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 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.Significance Statement Microglia support brain development, but the underlying mechanisms are not fully understood. Here, we show that mice deficient for inflammasome cascade protein genes, including Nlrp3, Casp1, Il-1r, and Gsdmd, develop behavior abnormalities characterized by hyperactivity and low anxiety. Lytic cell death occurs downstream of inflammasomes and was observed to appear in microglia in spatiotemporal and Casp1-dependent manners. Microglial death may be important for the proper differentiation of NPCs, as indicated by increased neuron numbers in specific regions of the brain in Casp1-deficient mice. Importantly, injection of NLRP3 and CASP1 inhibitors into pregnant mothers during this lytic death window resulted in offspring with behavior abnormalities. Overall, the death of discrete microglial subsets may be essential for proper NPC development and normal behaviors.

PMID:33414187 | DOI:10.1523/ENEURO.0342-20.2020

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