The Effect of Perinatal Hypoxia on White Matter Astrocytes

George Washington University, Washington DC

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Abstract

DESCRIPTION (provided by applicant): The general goal of this project is to understand the effects of brain injury due to hypoxia (HX) in the perinatal rodent; specifically this study will examine the astrocyte population of the subcortical white matter (WM) focusing on their development, their progeny and their ability to remove glutamate after HX. Altogether, my studies will define the specific effects of perinatal HX on astrocytes and the role of altered astrocyte development and function in WM injury. My results will not only shed light on crucial cellular and molecular mechanisms of WM injury and recovery, but may also assist in the development of new therapeutic approaches aimed at: i) enhancing WM recovery after early postnatal HX, and ii) reducing the long-term neurological sequelae associated with premature birth such as cerebral palsy, epilepsy, cognitive delay and learning disabilities. My overall hypothesis is that HX in the perinatal rodent induces changes in WM astrocyte function that directly affect oligodendrocyte integrity and development, and that this may be due to altered JAK/STAT signaling in astrocytes. I also hypothesize that HX promotes generation of oligodendrocytes from glial fibrillary acidic protein (GFAP)-expressing astrocytes. Therefore, I will determine the effect of HX on the expression of glial specific glutamate transporters GLAST and GLT-1 in the WM, and the ability of the WM to take up glutamate by two different approaches: electrophysiological characterization of WM astrocytes and uptake of radiolabled aspartate in WM crude membrane (synaptosome/gliosome) preparations. I will examine the effect of HX on JAK/STAT signaling in astrocytes and the effect of disrupting JAK/STAT signaling on the expression of GLAST and GLT-1. I will also perform lineage analysis studies, examining the progeny of GFAP- expressing astrocytes by utilizing an inducible Cre-recombinase system (hGFAP-Cre-ERT2 mouse) in which all progeny of GFAP-expressing cells are marked with a reporter to determine the contribution of these cells to WM recovery.