Infant mortality and morbidity associated with perinatal brain injury represent significant clinical problems, as both the cost of immediate medical care and long-term support continues to escalate. However, the mechanisms underlying neonatal brain damage are still poorly understood. In one model of brain injury, using the selective antagonist MK801, we have shown that blockade of the N-methyl-D-aspartate receptor (NMDAR) during a critical period in neonatal development will promote widespread injury throughout the forebrain. As the animal matures this window of vulnerability closes and the brain is no longer sensitive to MK801 treatment. Using tissue culture approaches, we have shown that neuronal injury following MK801 exposure is associated with decreased intracellular calcium. In similar preparations, we have demonstrated that agents that reduce intracellular calcium by mechanisms independent of NMDAR blockade also promote neuronal injury. However, what is not known is whether reductions in intracellular calcium during this window of vulnerability (regardless of mechanism) can lead to the same brain injury as MK801 treatment. We have recently shown that calcium binding proteins are not expressed in MK801-sensiitve neurons. In addition, these same neurons appear unable to buffer changes in calcium. Based on our in vitro observations, we hypothesize that MK801 exposure promotes neonatal brain injury by reducing intracellular calcium. We will address this hypothesis by using whole animal, brain slice and transgenic approaches. We will correlate changes in intracellular calcium with changes in markers of programmed cell death, to identify potential pathways. Because many drugs used in neonatal surgery act to lower intracellular calcium, understanding the mechanisms behind the selective toxicity of MK801 in neonates will help identify new therapeutic targets to protect from or cure brain injury in infants exposed to such agents during vulnerable periods. However, if our hypothesis is correct, maintaining calcium homeostasis may be generally important to neuronal survival during critical developmental periods and a loss of calcium homeostasis may be a significant factor contributing to diverse forms of perinatal brain injury. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS051632-01A2
Application #
7144790
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Hicks, Ramona R
Project Start
2006-06-01
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
1
Fiscal Year
2006
Total Cost
$317,886
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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Turner, Christopher Paul; DeBenedetto, Danielle; Ware, Emily et al. (2010) Postnatal exposure to MK801 induces selective changes in GAD67 or parvalbumin. Exp Brain Res 201:479-88
Turner, Christopher P; Ware, Emily; Stowe, Robert et al. (2010) Postnatal expression of GAD67. Neurochem Res 35:254-61
Gutierrez, S; Carnes, A; Finucane, B et al. (2010) Is age-dependent, ketamine-induced apoptosis in the rat somatosensory cortex influenced by temperature? Neuroscience 168:253-62
Lyall, Amanda; Swanson, John; Liu, Chun et al. (2009) Neonatal exposure to MK801 promotes prepulse-induced delay in startle response time in adult rats. Exp Brain Res 197:215-22
Turner, Christopher P; Debenedetto, Danielle; Ware, Emily et al. (2009) MK801-induced activated caspase-3 exhibits selective co-localization with GAD67. Neurosci Lett 462:152-6
Turner, Christopher P; Debenedetto, Danielle; Liu, Chun (2009) NMDAR blockade-induced neonatal brain injury: Reversal by the calcium channel agonist BayK 8644. Neurosci Lett 450:292-5
Bauer, Clayton T; Shtridelman, Yuri; Lema Tome, Carla M et al. (2008) Intraneuronal vesicular organelle transport changes with cell population density in vitro. Neurosci Lett 441:173-7
Ringler, Sarah L; Aye, Jamie; Byrne, Erica et al. (2008) Effects of disrupting calcium homeostasis on neuronal maturation: early inhibition and later recovery. Cell Mol Neurobiol 28:389-409
Lema Tome, Carla M; Miller, Ryan; Bauer, Clayton et al. (2008) Decline in age-dependent, MK801-induced injury coincides with developmental switch in parvalbumin expression: somatosensory and motor cortex. Dev Psychobiol 50:665-79

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