Attenuation of neurotoxicity in cortical cultures and hippocampal slices from E2F1 knockout mice

The E2F1 transcription factor modulates neuronal apoptosis induced by staur osporine, DNA damage and beta -amyloid. We demonstrate E2F1 involvement in neuronal death induced by the more physiological oxygen-glucose deprivation (OGD) in mouse cortical cultures and by anoxia in mouse hippocampal slices . E2F1(+/+) and (-/-) cultures were comparable, in that they contained simi lar neuronal densities, responded with similar increases in intracellular c alcium concentration ([Ca2+](i)) to glutamate receptor agonists, and showed similar NMDA receptor subunit mRNA expression levels for NR1, NR2A and NR2 B. Despite these similarities, E2F1(-/-) cultures were significantly less s usceptible to neuronal death than E2F1(+/+) cultures 24 and 48 h following 120-180 min of OGD. Furthermore, the absence of E2F1 significantly improved the ability of CA1 neurons in hippocampal slices to recover synaptic trans mission following a transient anoxic insult in vitro. These results, along with our finding that E2F1 mRNA levels are significantly increased followin g OGD, support a role for E2F1 in the modulation of OGD- and anoxia-induced neuronal death. These findings are consistent with studies showing that ov erexpression of E2F1 in postmitotic neurons causes neuronal degeneration an d the absence of E2F1 decreases infarct volume following cerebral ischemia.