Abstract 111: Membrane Lipid-Sensing Receptor MS4A Modulates Microglial Reparative Phenotype in Acute Germinal Matrix Hemorrhage-Intraventricular Hemorrhage (GMH-IVH)

Abstract

Background: GMH-IVH refers to spontaneous bleeding in the periventricular germinal zone and ventricles of an immature brain. Preterm infants with GMH-IVH often have lifelong neurologic deficits. Microglia play crucial roles during development; however, what role they play in neonatal cerebrovascular injury such as GMH-IVH is less known. Here we established a mouse GMH-IVH model and unveiled an immature brain-specific microglial response. Methods: GMH-IVH and adult intracerebral hemorrhage (ICH)-IVH were induced by blood injection into the caudate-putamen and periventricular region of postnatal day 5 and 8-week-old mice. Astrogliosis, myelin loss, MS4A receptor expression, neuron morphology, and spine density were evaluated by immunofluorescence and Golgi’s staining. Transcriptome of microglia was profiled by NanoString. Cx3cr1 CreER ; iDRT mice and PLX3397 treatment were used to deplete microglia. Cognitive and affective functions were evaluated. In vivo siRNA delivery was used to explore the mechanism underlying acute microglia reparative activation after GMH-IVH. Result: Astrogliosis and myelin loss were sustained till at least 8 weeks after GMH-IVH. Reduced neuronal dendritic complexity in the dentate gyrus and medial prefrontal cortex suggested compromised neuronal development in GMH-IVH. Upon adulthood, GMH-IVH mice had impaired cognitive and affective functions . Microglia showed heterogeneous phenotypes on day 3 after GMH-IVH. Interestingly, acute depletion of microglia aggravated myelin loss and neurobehavioral deficits, implying a beneficial role of these cells in the early stage of GMH-IVH. Compared with day 28 after GMH-IVH and day 3 after ICH-IVH, microglia at day 3 GMH-IVH uniquely upregulated lipid-sensing receptor MS4A. Inhibition of MS4A worsened long-term GMH-IVH outcomes. Conclusion: MS4A-expressing microglia are beneficial for GMH-IVH and targeting their responses could be a therapeutic approach for treating GMH-IVH.