488 Understanding astrocyte responses to perinatal white matter injury and their role in disease pathogenesis

Abstract

White matter injury (WMI) is a complication of preterm birth and a major cause of long-term neurological morbidity. The disease is characterized by reactive microgliosis and astrocytosis, defective oligodendrocyte maturation, and in severe cases, neuronal death. Reactive astrocytes are known to play important roles in the pathogenesis of many diseases, in some cases favoring repair and in others contributing to neurodegeneration. The specific nature of astrocyte reactivity after WMI remains obscure. Here we report the results of experiments aimed to define astrocyte polarization after white matter injury and its contribution to disease outcomes. WMI was induced in 2 day-old rat pups using a combination of hypoxic-ischemic and inflammatory insults. We used immunopanning to purify astrocytes from brains of injured and control rats. mRNA isolated from these cells was used for microfluidic qRT-PCR analysis of a panel of known markers of reactive astrocyte subtypes. In situ hybridization was used to define the spatial distribution of the reactive astrocytes within the rodent brain. In situ hybridization experiments demonstrate the presence of inflammatory reactive astrocytes in subcortical white matter tracts after WMI in our rodent disease model. qRT-PCR using mRNA from pre- and post-injury astrocytes reveals the temporal regulation of astrocyte reactivity over time after injury. Ongoing experiments using transgenic mice aim to modulate the astrocyte response to WMI and to quantify consequent changes in disease outcomes. We demonstrate the formation of inflammatory reactive astrocytes in a rodent model of WMI and present work in progress to characterize the astrocyte response in perinatal WMI. Should ongoing experiments demonstrate that the formation of inflammatory astrocytes is a pivotal step in WMI pathophysiology, this finding will open the door to new therapeutic strategies for the treatment of WMI.