Mechanisms of Excitotoxic Injury to Oligodendrocytes

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Periventricular leukomalacia (PVL) occurs in preterm infants suffering cerebral hypoxia/ischemia and/or prior exposure to maternal-fetal infection, both of which can involve excitotoxic preoligodendrocyte (preOL) injury. A central hypothesis in this Project is that a major factor in PVL is the induction of glutamate receptor (GluR)-mediated excitotoxicity in cells intrinsic to white matter (WM). We further hypothesize that the developmental status of GluRs increases susceptibility of the WM to excitotoxic injury. Our in vitro and in vivo models of excitotoxic injury demonstrated that premyelinating OLs (preOLs) are selectively vulnerable to excitotoxicity and hypoxic/ischemic injury at least in part due to a developmental overexpression of calcium (Ca2+)-permeable alpha amino-3-hydroxy-5-methyl-4-isox-azole propionate (AMPA) and kainate (KA) ionotropic GluRs. We have shown that these GluRs are similarly overexpressed on OLs in developing human WM during the developmental window of vulnerability to PVL (23-36 gestational weeks). Our pharmacologic studies in vivo and in vitro demonstrate that preOL excitotoxicity can be attenuated by Ca2+-permeable AMPA/KA receptor antagonists. We have recently extended our studies to address the role of GluRs on preOLs in the clinically relevant setting of recurrent episodes of hypoxia/ischemia, and show that subthreshold, sublethal excitotoxic injury sensitizes preOLs to injury, and that this phenomenon is AMPA/KA receptor-dependent. In the present proposal, we will characterize in-depth the developmental expression of GluRs in normal human WM and determine whether expression is altered following PVL (Aim 1). We will determine alterations in GluR function, expression and signaling following lethal OGD and sublethal OGD in preOLs in vitro (Aim 2). In parallel, we will determine alterations in GluR function and expression following lethal hypoxic/ischemic injury and sublethal hypoxia in vivo (Aim 3). Finally, we aim to characterize expression of GluRs on other cell types in white matter during the window of vulnerability to hypoxic/ischemic white matter injury, and to evaluate GluR alterations in these cells following lethal hypoxia/ischemia or sublethal hypoxia in vivo (Aim4). Throughout the proposal, we examine mechanism of action and efficacy of therapeutic strategies targeting GluRs. The overall goal of this project is to gain improved understanding of the role of GluRs in PVL in order to design new age-specific therapies.