Periventricular leukomalacia (PVL) occurs in preterm infants suffering cerebral hypoxia/ischemia and/or prior exposure to maternal-fetal infection (see Introductory Overview), both of which can involve excitotoxic oligodendrocyte (OL) injury. The overall hypothesis of this project is that excitotoxicity via activation of glutamate receptors (GluRs) on O4+ OL precursors and immature O1+ OLs (collectively referred to as preOLs) is a major cause of subsequent cerebral hypomyelination, the hallmark of PVL, and that this excitotoxicity can be prevented. Excitotoxicity to preOLs is critically mediated by ionotropic GluRs (iGluRs), which we have previously demonstrated to be overexpressed during the developmental window of vulnerability to excitotoxicity in rodent and in human white matter. During the past funding period, we have developed in vitro and in vivo models of excitotoxic OL injury, and have demonstrated that the preOLs are selectively vulnerable to excitotoxicity due to a developmental overexpression of calcium (Ca2+)-permeable -amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate (KA) receptors, (AMPA/KARs) subtypes of iGluRs. We have recently demonstrated that GluRs are similarly overexpressed on human OLs in white matter at ages characterized by susceptibility to PVL. We have shown that Ca2+-permeable AMPA/KA receptors lacking the GluR2 subunit play a major role in preOL excitotoxicity and that their activation triggers mitochondrial dysfunction and intracellular free radical accumulation, thus linking the two major downstream mechanisms of preOL injury in PVL (see Introductory Overview). This work has led to the discovery that topiramate, a clinically available FDA-approved anticonvulsant with AMPAR antagonist properties, is effective as a post-treatment in both our in vivo and in vitro models of PVL. PVL often occurs in the setting of an infant suffering repeated, often subtle, hypoxic/ischemic or inflammatory events (see Introductory Overview). We have developed novel in vivo and in vitro recurrent injury models and show that sub-threshold hypoxia/ischemia or oxygen-glucose deprivation appears to “prime” OLs for enhanced injury by upregulating GluR Ca2+ permeability before a recurrent insult. The present project focuses further on characterizing the developmental expression of GluRs in human white matter and their alterations in PVL. We examine in greater detail the role of Ca2+-permeable GluRs and mitochondrial dysfunction in oxygen-glucose deprivation (OGD) and hypoxic/ischemic preOL injury as well as in the priming phenomenon observed with recurrent insults. Finally, we now consider the role of GluRs on other cellular elements of white matter in white matter injury in our in vivo PVL models. Our overall goal is to identify novel GluR-mediated mechanisms of injury as well as to determine the status of GluRs in developing human white matter to facilitate translation of our findings to potentially clinically useful therapeutic strategies.
