Differential expression of apoptotic protease-activating factor-1 and caspase-3 genes and susceptibility to apoptosis during brain development and after traumatic brain injury

Neuronal apoptosis plays an essential role in early brain development and c ontributes to secondary neuronal loss after acute brain injury. Recent stud ies have provided evidence that neuronal susceptibility to apoptosis induce d by traumatic or ischemic injury decreases during brain development. Howev er, the molecular mechanisms responsible for this age-dependent phenomenon remain unclear. Here we demonstrate that, during brain maturation, the pote ntial of the intrinsic apoptotic pathway is progressively reduced and that such repression is associated with downregulation of apoptotic protease-act ivating factor-1 (Apaf-1) and caspase-3 gene expression. A similar decline in apoptotic susceptibility associated with downregulation of Apaf-1 expres sion as a function of developmental age was also found in cultured primary rat cortical neurons. Injury-induced cytochrome c-specific cleavage of casp ase-9 followed by activation of caspase-3 in mature brain correlated with m arked increases in Apaf-1 and caspase-3 mRNA and protein expression. These results suggest that differential expression of Apaf-1 and caspase-3 genes may underlie regulation of apoptotic susceptibility during brain developmen t, as well as after acute injury to mature brain, through the intrinsic pat hway of caspase activation.