Regulation of microglial plasticity by TLR4 and microRNAs

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 DESCRIPTION (provided by applicant): The adult CNS can adapt to and compensate for deficits in neurologic function after CNS injury or neurodegenerative disease, an effect that contributes to typically less severe clinical symptoms than the magnitude of neuronal damage. Microglia, CNS resident immune cells, play fundamental roles in brain health and disease and are essential neuron partners, but little is understood about how their activities contribute to endogenous mechanisms of CNS repair and adaptation to a chronic neuroinflammatory insult. Here we focus on the mechanisms that control microglial transition from the pro-inflammatory to the anti- inflammatory/neurosupportive phenotype over the course of a chronic disease that affects millions of Americans. We will use exposure to chronic intermittent hypoxia (CIH), a hallmark of sleep apnea that causes significant cognitive and learning impairments in humans and animal models, and that is experienced in more than half of patients with other neurological diseases and injuries. We have identified two primary phases of CIH neuropathology, an acute pro-inflammatory phase that coincides with hippocampal neuron loss and impaired hippocampal plasticity (long-term potentiation; LTP), and a late phase in which microglia produce neurotrophic factors and neurocognitive behaviors partially recover. Our data suggest that the signaling activities of the Toll-like receptor 4 (TLR4), an innate immune receptor that is most often associated with pro- inflammatory microglial responses, may contribute to the beneficial effects of microglia late in CIH pathology. We find TLR4-dependent upregulation of an anti-inflammatory microRNA during CIH that functions to suppress the pro-inflammatory activities of the canonical MyD88-dependent TLR4 signaling pathway. TLR4 signaling also promotes BDNF production which is required for hippocampal LTP and neuron survival, and we find that microglial BDNF expression temporally mirrors early hippocampal LTP loss and later recovery of learning during CIH. Thus, our overarching hypothesis is that early pro-inflammatory TLR4 signaling is later repressed by TLR4-dependent miRNAs that ultimately promote microglial transition to the neurotrophic phenotype, helping to limit neuronal damage and support recovery of hippocampal neuroplasticity during continued CIH pathology. Four specific aims will be pursued using the shared power of genetic/biochemical studies in transgenic mice, multi-color flow cytometry, and hippocampal slice electrophysiology. The aims will test the role of TLR4 and its signaling pathways in orchestrating the beneficial effects of microglia, as well as the requirement for microglial BDNF in limiting neuronal loss and recovering hippocampal plasticity in the late phase of CIH. Results from these studies will identify mechanisms by which microglia adapt to enduring neuroinflammatory disease to limit injury and help promote recovery of neuronal function. Mechanisms identified here may be harnessed for therapeutic benefit to enhance ongoing, endogenous neural repair mechanisms for many disorders in which intermittent hypoxia and/or microglia play a role.