Excitotoxic injury to developing oligodendrocytes

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Substantial evidence implicates hypoxic/ischemic white matter injury as a cause of periventricular leukomalacia (PVL). The excitatory neurotransmitter glutamate is released from axons and glia under hypoxic/ischemic conditions. We now show that glutamate can be toxic to developing oligodendrocytes (OLs) via interaction with their alpha- amino-3-hydroxy-5-methyl-4e-isox-azole propionate (AMPA) and kainate receptors. Preliminary in vivo and in vitro results show that vulnerability to AMPA/kainate may be developmentally specific, enhanced in immature stages of OL differentiation. Furthermore, we now show that the developmental window of vulnerability to hypoxic/ischemic white matter injury parallels that for toxicity of AMPA agonists. A role for AMPA/kainate receptor-mediated toxicity in hypoxic/ischemic injury in the immature brain is supported by the observation that systemic treatment with the AMPA/kainate antagonist 6- nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (NBQX) following hypoxia/ischemia attenuates white matter injury in the immature rat. The present project aims to understand the basis for the developmental specificity of AMPA/kainate injury to OLs, and whether this may be an important component of injury in the immature brain in vivo. The overall hypothesis of Project 4 is that maturation-dependent vulnerability of OLs to AMPA/kainate receptor-mediated excitotoxicity is an important cause of OL death in immature cerebral white matter, and thereby a potentially important factor in the pathogenesis of PVL. Aim 1. To determine whether the maturation-dependent vulnerability of OLs to AMPA/kainate toxicity relates to developmental differences in expression of AMPA/kainate receptors in OLs in vitro and in vivo. We will establish the developmental profile of AMPA/kainate receptors in primarily OLs; Aim 2. To characterize the mechanism of AMPA/kainate receptor- mediated toxicity in developing OLs. We will identify maturational differences in OL vulnerability and determine whether Ca++ influx and free radicals are mediating the death of developing OLs in vitro; Aim 3. To determine whether white matter injury induced by intracerebral injection of AMPA/kainate agonists is maturation dependent in rodent model of PVL; and Aim 4. To determine the maturational vulnerability of OLS to cerebral hypoxia/ischemia in the rat and the role of AMPA/kainate receptors in this vulnerability and whether glutamate antagonists represents a potential means of prevention of hypoxic- ischemic OL injury in the immature brain. The long term goal of this project is to define age-specific therapeutic strategies for the treatment and prevention of PVL.