Differential effects of Bcl-2 overexpression on hippocampal CA1 neurons and dentate granule cells following hypoxic ischemia in adult mice

In contrast to its known anti-apoptotic activity in sympathetic neurons, im mortal neuronal cell lines, and primary cultured immature neurons of the ce ntral nervous system (CNS), the role of Bcl-2 in CNS neurons in the adult b rain is poorly understood. In the present study, we examined effects of ove rexpression of Bcl-2 on selective neuronal death of the hippocampal CA1 neu rons and the dentate granule cells induced by hypoxic ischemia in adult tra nsgenic mice overexpressing human Bcl-2 under the control of neuron-specifi c enolase (NSE-hbcl-2), At the light microscopic level, numbers of TUNEL-po sitive cells with pyknotic nuclei were observed in the CA1 subfield of NSE- hbcl-2 transgenic mice, as well as that of wild-type mice, after hypoxic is chemic insult, although the onset of neuronal death was apparently delayed in NSE-hbcl-2 transgenic mice. The electron microscopic studies showed that morphological changes of the degenerating CA1 neurons from both groups wer e clearly distinct from ordinary apoptosis. In contrast, a significant amou nt of degenerating dentate granule cells from wild-type but not from transg enic mice had typical apoptotic nuclei by the treatment. The activation of caspase-3 was detected in the dentate granule cells but not that of the CA1 neurons. These results indicate that the overexpression of Bcl-2 effective ly suppressed dentate granule cell apoptosis but only delayed cell death of the CA1 neurons induced by hypoxic ischemia, suggesting the occurrence of a non-apoptotic, caspase-3-independent mechanism for neuronal death in the CA1 subfield, (C) 1999 Wiley-Liss, Inc.