Attenuation of neurotoxicity in cortical cultures and hippocampal slices from E2F1 knockout mice.
The E2F1 transcription factor modulates neuronal apoptosis induced by staurosporine, 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 similar neuronal densities, responded with similar increases in intracellular calcium concentration ([Ca(2+)]i) to glutamate receptor agonists, and showed similar NMDA receptor subunit mRNA expression levels for NR1, NR2A and NR2B. Despite these similarities, E2F1(-/-) cultures were significantly less susceptible 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 transmission following a transient anoxic insult in vitro. These results, along with our finding that E2F1 mRNA levels are significantly increased following OGD, support a role for E2F1 in the modulation of OGD- and anoxia-induced neuronal death. These findings are consistent with studies showing that overexpression of E2F1 in postmitotic neurons causes neuronal degeneration and the absence of E2F1 decreases infarct volume following cerebral ischemia.
Gendron
T F
TF
Institute for Biological Sciences, National Research Council Canada, Ottawa, Ontario, Canada. tania.gendron@nrc.ca
Mealing
G A
GA
Paris
J
J
Lou
A
A
Edwards
A
A
Hou
S T
ST
MacManus
J P
JP
Hakim
A M
AM
Morley
P
P
D000818:Animals; D002118:Calcium / Q000378:metabolism; D018797:Cell Cycle Proteins; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000502:physiology*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000502:physiology*; D005333:Fetus; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; D005947:Glucose; D002118:Calcium