Long term effect of early postnatal disruption of microglial development by Casp8 deletion Sunja Kim1, Bianca Barth1, Gus Wright1, Danielle Michaud1, William H. Griffith2, and Jianrong Li1,* 1Dept. of Vet. Integ. Biosci, Texas A&M Univ, College Station; 2Dept. of Neurosci. & Exp. Ther, Texas A&M Health Sci. Center, Bryan, TX
Microglia, the primary immune cells of the CNS, undergo rapid expansion during early postnatal development. They actively phagocytose apoptotic cells and refine neural circuits by modulating synapse formation and elimination. Recent studies have suggested that early life infection/stress can profoundly alter microglial activities, resulting in increased vulnerability for neuropsychiatric disorders and neurodegenerative diseases in adulthood. However, intrinsic mechanisms that regulate postnatal microglial development and functions remain largely undefined. Here we report that caspase-8 is predominantly expressed in microglia in the CNS and acts as a crucial checkpoint for microglial immune activation. To investigate the in vivo function of microglial caspase-8, we generated tamoxifen-inducible Cx3cr1CreERT2 promoter driven Casp8 conditional mice. Ablation of Casp8 during the first postnatal week resulted in markedly decreased microglial density across multiple brain regions and profound microglial activation when analyzed at postnatal day 10 (P10). Interestingly, by 1 month of age the density and morphology of microglia were indistinguishable between Casp8 conditional knockout and littermate controls. Transcriptome profiling analyses of P10 forebrains as well as isolated microglia at P8 revealed that caspase-8 deficiency resulted in activation of anti-viral/anti-bacterial pattern receptor recognition signals and antigen presentation profiles. Ingenuity pathway analysis demonstrated that these upregulated gene signatures overlap with transcriptome profiles of several brain diseases including viral infection, neurodegenerative diseases, and experimental autoimmune diseases. Preliminary analysis of neurobehaviors of adult mice that received tamoxifen at neonatal stage suggests behavioral alterations in Casp8 conditional knockout mice as compared to littermate controls. Taken together, our study identifies a non-canonical function of caspase-8 in microglial activation during development and suggests that early-life disruption of microglial caspase-8 function may have long-term adverse effects.
Supported in part by NIH R21NS093487
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