Hypoxia-ischemia damages the brain in a developmental stage-specific and region selective manner. Evidence suggests that selective cellular vulnerability contributes to differing patterns of age-related hypoxicic schemic injury. In a rodent model of human periventricular white matter injury, we determined that early hypoxia-ischemia leads to the selective cell death of sub-plate neurons, a cell population unique to the developing brain. Sub-plate neurons are required for activity-dependent formation, refinement and maturation of patterned thalamocortical connections, and may play a role in the unique capacity of the neonatal brain for plasticity during defined critical periods. We have developed a method for purifying sub-plate neurons, representing the first lamina-specific cortical neuronal cultures and have reported the factors that promote sub-plate neuron survival including a novel p75NTR dependent ceramide signaling pathway. Consistent with their selective vulnerability in vivo, cultured sub-plate neurons are more sensitive to oxygen-glucose deprivation than age matched mixed cortical neuronal cultures. Our objectives in this proposal are 1) to determine the significance of selective sub-plate neuron death for subsequent cortical plasticity and 2) utilize purified sub-plate neurons to determine the mechanism of selective sub-plate neuron vulnerability. We hypothesize that selective sub-plate neuron death following early hypoxia-ischemia impairs activity-dependent cortical plasticity. We will quantify activity dependent cortical plasticity following early hypoxia-ischemia and interventions that prevent sub-plate neuron cell death. We hypothesize further that sub-plate neuron selective vulnerability results from altered neurotrophin-mediated p75NTR-dependent signaling and we will investigate this with immunopurified cultures of sub-plate neurons exposed to oxygen glucose deprivation. Finally, we hypothesize that treatments that protect sub-plate neurons in vitro will also prevent sub-plate neuron cell death following early hypoxia ischemia. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research (K02)
Project #
1K02NS047098-01A1
Application #
6866027
Study Section
NST-2 Subcommittee (NST)
Program Officer
Kleitman, Naomi
Project Start
2004-09-20
Project End
2009-06-30
Budget Start
2004-09-20
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$161,406
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Nguyen, Vien; McQuillen, Patrick S (2010) AMPA and metabotropic excitoxicity explain subplate neuron vulnerability. Neurobiol Dis 37:195-207
McQuillen, Patrick S; Miller, Steven P (2010) Congenital heart disease and brain development. Ann N Y Acad Sci 1184:68-86
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McQuillen, Patrick S; Nishimoto, Michael S; Bottrell, Christine L et al. (2007) Regional and central venous oxygen saturation monitoring following pediatric cardiac surgery: concordance and association with clinical variables. Pediatr Crit Care Med 8:154-60
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McQuillen, P S; Ferriero, D M (2005) Perinatal subplate neuron injury: implications for cortical development and plasticity. Brain Pathol 15:250-60