Immature white matter is subject to ischemic injury during the development of the lesion called periventricular leukomalacia, which is the major pathology, associated with cerebral palsy. The goal of this research is to understand the mechanisms that underlie acute ischemic cell death in immature white matter glial cells. Fluorescent ion-sensitive dyes will be loaded into glial cells in the neonatal rat optic nerve and used to measure changes in intracellular [Ca2+], [Na+] and pH during ischemia in situ. These ionic changes will be correlated to the occurrence of cell death and any casual relationships will be determined. Ionic substitution and drug application will be used to probe mechanisms that underlie ionic derangements that occur in neonatal white matter glia during ischemia. Glial cell types within neonatal white matter are likely to show acute changes in intracellular ions during ischemia due to quite different mechanisms. Live staining of glia in situ will be applied to distinguish astrocytes from oligodendrocytes, allowing both the characteristics of cell death and ionic distribution during ischemia to be analyzed in the two major types of marcoglia present in the CNS. Experiments will test three hypotheses: 1) Acute ischemic astrocyte death at the point in development most at risk (P10nRON), results from Na+ -influx and cell swelling. 2) Na+ -influx/cell swelling also accounts for a significant proportion of acute death of oligodendrocytes and of less mature astrocytes. 3) Non-NMDA glutamate receptors mediate only a proportion of toxic Ca2+ -influx into oligodendroglial during ischemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044875-02
Application #
6640712
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Leblanc, Gabrielle G
Project Start
2002-05-01
Project End
2007-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$230,850
Indirect Cost
Name
University of Leicester
Department
Type
DUNS #
226742724
City
Leicester
State
Country
United Kingdom
Zip Code
LE7 9-HR
Alix, James J P; Zammit, Christian; Riddle, Art et al. (2012) Central axons preparing to myelinate are highly sensitive [corrected] to ischemic injury. Ann Neurol 72:936-51
Domingues, Antonio M de Jesus; Neugebauer, Karla M; Fern, Robert (2011) Identification of four functional NR3B isoforms in developing white matter reveals unexpected diversity among glutamate receptors. J Neurochem 117:449-60
Quimby, Samuel; Fern, Robert (2011) Novel morphological features of developing white matter pericytes and rapid scavenging of reactive oxygen species in the neighbouring endothelia. J Anat 219:65-77
Domingues, Antonio Miguel de Jesus; Taylor, Mark; Fern, Robert (2010) Glia as transmitter sources and sensors in health and disease. Neurochem Int 57:359-66
Alix, James J P; Fern, Robert (2009) Glutamate receptor-mediated ischemic injury of premyelinated central axons. Ann Neurol 66:682-93
Lauer, Richard T; Prosser, Laura A (2009) Use of the Teager-Kaiser Energy operator for muscle activity detection in children. Ann Biomed Eng 37:1584-93
Alix, James J P; Dolphin, Annette C; Fern, Robert (2008) Vesicular apparatus, including functional calcium channels, are present in developing rodent optic nerve axons and are required for normal node of Ranvier formation. J Physiol 586:4069-89
Salter, Michael G; Fern, Robert (2008) The mechanisms of acute ischemic injury in the cell processes of developing white matter astrocytes. J Cereb Blood Flow Metab 28:588-601
Shannon, Clare; Salter, Mike; Fern, Robert (2007) GFP imaging of live astrocytes: regional differences in the effects of ischaemia upon astrocytes. J Anat 210:684-92
Domercq, Maria; Sanchez-Gomez, Maria Victoria; Sherwin, Catherine et al. (2007) System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes. J Immunol 178:6549-56

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