Loss of microglial Stat3 signaling in early postnatal development affects synaptic plasticity Hsueh C. Lu1*, Bianca Barth1*, Sunja Kim1*, Adam Bowling1, Danielle Michaud1, Kranti Konganti2, James Cai1, William Griffith3 and Jianrong Li1,# 1Department of Veterinary Integrative Biosciences, 2Institute for Genome Sciences and Society, Texas A&M University, 3Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center. *Equal contribution
Microglia play critical roles in maturation and refinement of neural networks during postnatal brain development. Although microglia have been shown to arise from the yolk sac and colonize the CNS during early embryogenesis and undergo expansion in the first two postnatal weeks, it is less clear what intrinsic signals regulate postnatal microglia and how disruption of microglia at this development stage affects brain function. Here we report that signal transducer and activator of transcription 3 (Stat3) regulates microglial survival and activation in the developing brain and that neonatal disruption of Stat3 signaling in microglia results in impaired hippocampal synapse plasticity in adult. Cx3cr1CreERT2/+:Stat3loxPmice were generated to achieve inducible deletion of exon 22 ofthe Stat3 gene in microglia, which results in truncated Stat3 protein incapable of nuclear translocation. Neonatal Stat3 ablation caused spontaneous microglia activation and transient loss of microglial cell population at postnatal day 10 (P10), which was recovered by P30. The transient decrease of microglia at P7-P10 was associated with increased innate immune responses including type I interferon signaling, complement pathways and cytokine/chemokine production as determined by RNA-seq analysis of acutely isolated microglia at P7. Consistently, Stat3 mutant microglia produced significantly higher levels of proinflammatory cytokines than wild-type microglia when challenged. Moreover, transcriptome analysis also revealed a role for Stat3 in DNA repair and long-term potentiation. Dystrophic dendrites of cortical pyramidal neurons were observed in the mutant mice but not littermate controls, suggesting that dysfunctional microglia impact on neuronal functions. Electrophysiological analysis of adult hippocampal slices revealed impaired hippocampal long-term potentiation in these Stat3 mutant mice. Collectively, our data demonstrate that Stat3 signaling plays an essential role in postnatal microglial development, and highlight that disruption of microglial function at critical developmental stages may have long-term neurological impact.
Supported in part by NIH R01NS060017 and the National Multiple Sclerosis Society research grants RG1507.
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