Periventricular leukomalacia (PVL), the most common pathology of cerebral palsy, consists of focal and diffuse white matter lesions with prominent oligodendrocyte (OL) loss. Hypoxic/ischemic white matter injury is implicated as a major cause of PVL. Currently there is limited understanding of the mechanism of this age specific white matter injury and therefore no preventive treatment, despite its increasing prevalence with improved survival of premature babies. The overall aim of this project is to better understand the developmentally specific mechanism of OL injury in PVL and to explore the potential role of glutamate antagonists in treatment. The long term goal of this research is to provide a foundation for in depth study of the mechanism of injury in PVL and thus to find a preventive treatment. Under hypoxic/ischemic conditions axons and glia are known to release the excitatory neurotransmitter glutamate, which has been shown to be toxic to OLs in vitro. While OLs do not express glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype, they do express non-NMDA glutamate receptors. We have developed a rat model of glutamate-induced injury to developing white matter, utilizing stereotactic injections of the glutamate agonist alpha-amino-3-hydroxy-5-methyl-4-isox-azole propionate (AMPA). In this model, we demonstrated a critical window of development during which toxicity is exacerbated. Extending these results to a rat model of hypoxia/ischemia we demonstrated a highly selective white matter injury at a similar age. In addition, we identified the presence of AMPA receptors in the white matter during this age window and demonstrated that the white matter injury in both models can be blocked by the AMPA antagonist NBQX. These results indicate the presence of receptor- mediated excitotoxic injury in hypoxia/ischemia, provide evidence for increased susceptibility to injury during a specific stage of OL development, and suggest a possible method for treatment. However, neither the developmental stage of OLs most affected, or the characteristics responsible for the maturational vulnerability, or the action of glutamate antagonists on white matter in vivo is well understood. Therefore, the goal of this project is to utilize our animal models to characterize: 1) the time course and cellular specificity of immature OL injury in the developing brain, 2) the presence and subtype composition of glutamate receptors on OLs during this vulnerable period, and 3) the effects of glutamate receptors agonists and antagonists on white matter injury and development.
| Talos, Delia M; Follett, Pamela L; Folkerth, Rebecca D et al. (2006) Developmental regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. II. Human cerebral white matter and cortex. J Comp Neurol 497:61-77 |
| Talos, Delia M; Fishman, Rachel E; Park, Hyunkyung et al. (2006) Developmental regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. I. Rodent cerebral white matter and cortex. J Comp Neurol 497:42-60 |
| Follett, Pamela L; Deng, Wenbin; Dai, Weimin et al. (2004) Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate. J Neurosci 24:4412-20 |
