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The role of Bax in glutamate-induced nerve cell death
R Dargusch1, D Piasecki, S Tan
1Laboratory of Cellular Neurobiology, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Abstract:
The role of the Bax gene product was examined in three forms of cortical nerve cell death in primary cultures. These include spontaneous cell death, oxidative glutamate toxicity, in which exogenous glutamate inhibits cystine uptake resulting in toxic oxidative stress, and ionotropic glutamate receptor-mediated excitotoxicity following a brief exposure to 10 microM glutamate. Primary cortical and hippocampal neuron cultures were established from embryos of Bax -/+ x Bax -/+ matings and the embryos genotyped and assayed for cell death in the three experimental paradigms. Cell death induced by oxidative glutamate toxicity and glutamate-mediated excitotoxicity was not altered in the Bax -/- homozygous knockout animals. In contrast, there was an approximately 50% inhibition of spontaneous cell death. These results suggest that a classical Bax-dependent apoptotic pathway contributes to the spontaneous cell death that takes place when nerve cells are initially exposed to cell culture conditions. A Bax-dependent programmed cell death pathway is not, however, utilized in oxidative glutamate toxicity and NMDA receptor-mediated excitotoxicity following a brief exposure to low concentrations of glutamate.
Insights
The Bax gene product partially inhibits spontaneous nerve cell death in cultures. However, Bax does not affect cell death from oxidative glutamate toxicity or excitotoxicity.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Nerve cell death is crucial in neurodevelopment and disease.
- The Bax gene product is a key mediator of apoptosis.
- Understanding Bax's role in different cell death pathways is essential.
Purpose of the Study:
- To investigate the role of the Bax gene product in three distinct forms of cortical nerve cell death.
- To differentiate Bax-dependent and Bax-independent cell death mechanisms in neurons.
Main Methods:
- Primary cortical and hippocampal neuron cultures were derived from Bax heterozygous mouse matings.
- Neurons were genotyped for Bax.
- Cell death was assessed in response to spontaneous conditions, oxidative glutamate toxicity, and ionotropic glutamate receptor-mediated excitotoxicity.
Main Results:
- Bax knockout (Bax-/-) did not alter cell death induced by oxidative glutamate toxicity.
- Bax knockout (Bax-/-) did not alter cell death induced by glutamate-mediated excitotoxicity.
- Spontaneous cell death was reduced by approximately 50% in Bax knockout (Bax-/-) neurons.
Conclusions:
- A classical Bax-dependent apoptotic pathway contributes to spontaneous nerve cell death in primary cultures.
- Bax-dependent programmed cell death is not involved in oxidative glutamate toxicity or brief glutamate excitotoxicity.
- These findings differentiate the mechanisms of neuronal cell death and highlight the specific role of Bax.