The goal of the proposed research is to determine the long-term protective properties of caspase-3 blockade in mice subjected to hypoxia-ischemia (H-I) as neonates. Neonatal H-I results in necrotic and apoptotic cell death; brain-derived neurotrophic factor (BDNF)protects both neural tissue and behavioral function following H-I in rats. The first objective of the proposed research is to determine the effectiveness of BDNF pre-treatment in providing long-term protection of brain tissue and behavior following neonatal H-I in mice. The second objective is to determine relationships among regional and cellular brain tissue measures, spatial memory function, and sensory-motor abilities in two strains of mice with mutations in the caspase-3 activation pathway (Bax and caspase-3 knockout). The third objective is to examine brain injury, spatial memory, and sensory-motor performance in Bax and caspase-3 knockout strains following neonatal H-I. The Levine H-I method (unilateral carotid ligation followed by reduced oxygen) will be performed on postnatal day 7 (PN7) mice. Spatial memory will be tested in a Morris water maze task and sensory-motor abilities will be tested at PN 30-45 and at PN85-100. After behavioral testing, quantitative regional volumes of hippocampus and cortex and density of CA1neurons in the hippocampus will be assessed stereologically. Detailed analyses of the effects of caspase-3 inhibition via pharmacological or genetic manipulation will be useful in the further development of neural and behavioral protective agents and strategies following neonatal H-I.
