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The Journal of Neuroscience, August 1, 2007, 27(31):8238-8249; doi:10.1523/JNEUROSCI.1984-07.2007

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Neurobiology of Disease
Mitochondrial and Plasma Membrane Potential of Cultured Cerebellar Neurons during Glutamate-Induced Necrosis, Apoptosis, and Tolerance

Manus W. Ward,^1 * Heinrich J. Huber,^1,2 * Petronela Weisová,¹ Heiko Düssmann,¹ David G. Nicholls,³ and Jochen H. M. Prehn¹

¹Department of Physiology and Medical Physics and RCSI Neuroscience Research Centre, Royal College of Surgeons in Ireland, Dublin 2, Ireland, ²Siemens Medical Division, Siemens Ireland, Dublin 2, Ireland, and ³Buck Institute for Age Research, Mitochondrial Physiology, Novato, California 94945

Correspondence should be addressed to Dr. Jochen H. M. Prehn, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. Email: prehn{at}rcsi.ie

A failure of mitochondrial bioenergetics has been shown to be closely associated with the onset of apoptotic and necrotic neuronal injury. Here, we developed an automated computational model that interprets the single-cell fluorescence for tetramethylrhodamine methyl ester (TMRM) as a consequence of changes in either _m or _p, thus allowing for the characterization of responses for populations of single cells and subsequent statistical analysis. Necrotic injury triggered by prolonged glutamate excitation resulted in a rapid monophasic or biphasic loss of _m that was closely associated with a loss of _p and a rapid decrease in neuronal NADPH and ATP levels. Delayed apoptotic injury, induced by transient glutamate excitation, resulted in a small, reversible decrease in TMRM fluorescence, followed by a sustained hyperpolarization of _m as confirmed using the _p-sensitive anionic probe DiBAC₂(3). This hyperpolarization of _m was closely associated with a significant increase in neuronal glucose uptake, NADPH availability, and ATP levels. Statistical analysis of the changes in _m or _p at a single-cell level revealed two major correlations; those neurons displaying a more pronounced depolarization of _p during the initial phase of glutamate excitation entered apoptosis more rapidly, and neurons that displayed a more pronounced hyperpolarization of _m after glutamate excitation survived longer. Indeed, those neurons that were tolerant to transient glutamate excitation (18%) showed the most significant increases in _m. Our results indicate that a hyperpolarization of _m is associated with increased glucose uptake, NADPH availability, and survival responses during excitotoxic injury.

Key words: excitotoxicity; mitochondria; modeling; plasma and mitochondrial membrane potential; bioenergetics; necrosis

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Received Feb. 26, 2007; revised June 11, 2007; accepted June 13, 2007.

Correspondence should be addressed to Dr. Jochen H. M. Prehn, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. Email: prehn{at}rcsi.ie

This article has been cited by other articles:

				A. V. Zhdanov, M. W. Ward, J. H. M. Prehn, and D. B. Papkovsky Dynamics of Intracellular Oxygen in PC12 Cells upon Stimulation of Neurotransmission J. Biol. Chem., February 29, 2008; 283(9): 5650 - 5661. [Abstract] [Full Text] [PDF]

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