Cerebral white matter (WM) is damaged in many neurologic disorders, including focal ischemia, perinatal brain injury, trauma, and multiple sclerosis. During the previous funding period, we and others established that oligodendrocytes (OLs) are highly vulnerable to over activation of AMPA/kainate (AMPA/KA) glutamate receptors. Unexpectedly, we found that AMPA/KA antagonists during oxygen-glucose deprivation protect axons as well as OLs, in oligodendrocyte-axon co-cultures and in WM brain slices. Since isolated axons are not vulnerable to glutamate receptor activation, the mechanisms of excitotoxic axon injury remain unknown. We will examine the hypothesis that over activation of AMPA/KA receptors on oligodendrocytes during oxygen-glucose deprivation contributes to damage of myelinated axons, and this involves release of reactive oxygen species (ROS). We have developed two new models to study these cellular interactions (a) a cell culture system in which isolated axons and oligodendrocytes are much more vulnerable to hypoxic and excitotoxic insults than either cell type alone, and (b) an acute brain slice model which allows measurement of white matter conduction together with visualization of axon and oligodendrocyte morphology. Using these models we will determine the role of oligodendrocyte glutamate receptor activation in axon injury, and assess potential injury pathways involving reactive oxygen species. Results of these studies may suggest treatment approaches for diseases, which share common pathology in central white matter.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036265-05
Application #
6802278
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Jacobs, Tom P
Project Start
1997-09-10
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
5
Fiscal Year
2004
Total Cost
$353,813
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Vadivelu, Sudhakar; Stewart, Todd J; Qu, Yun et al. (2015) NG2+ progenitors derived from embryonic stem cells penetrate glial scar and promote axonal outgrowth into white matter after spinal cord injury. Stem Cells Transl Med 4:401-11
Hyrc, Krzysztof L; Minta, Akwasi; Escamilla, P Rogelio et al. (2013) Synthesis and properties of Asante Calcium Red--a novel family of long excitation wavelength calcium indicators. Cell Calcium 54:320-33
Shen, Hua; Hyrc, Krzysztof L; Goldberg, Mark P (2013) Maintaining energy homeostasis is an essential component of Wld(S)-mediated axon protection. Neurobiol Dis 59:69-79
Shen, Hua; Goldberg, Mark P (2012) Creatine pretreatment protects cortical axons from energy depletion in vitro. Neurobiol Dis 47:184-93
Kim, Euysoo; Hyrc, Krzysztof L; Speck, Judith et al. (2011) Missense mutations in Otopetrin 1 affect subcellular localization and inhibition of purinergic signaling in vestibular supporting cells. Mol Cell Neurosci 46:655-61
Zeng, Chenbo; Vangveravong, Suwanna; Jones, Lynne A et al. (2011) Characterization and evaluation of two novel fluorescent sigma-2 receptor ligands as proliferation probes. Mol Imaging 10:420-33
Crawford, Devon C; Chang, Chun Yun; Hyrc, Krzysztof L et al. (2011) Calcium-independent inhibitory G-protein signaling induces persistent presynaptic muting of hippocampal synapses. J Neurosci 31:979-91
McIver, S R; Muccigrosso, M; Gonzales, E R et al. (2010) Oligodendrocyte degeneration and recovery after focal cerebral ischemia. Neuroscience 169:1364-75
Pitt, David; Gonzales, Ernesto; Cross, Anne H et al. (2010) Dysmyelinated axons in shiverer mice are highly vulnerable to alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated toxicity. Brain Res 1309:146-54
Kim, Euysoo; Hyrc, Krzysztof L; Speck, Judith et al. (2010) Regulation of cellular calcium in vestibular supporting cells by otopetrin 1. J Neurophysiol 104:3439-50

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