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The Journal of Neuroscience, May 7, 2008, 28(19):5029-5039; doi:10.1523/JNEUROSCI.5069-07.2008

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Cellular/Molecular
Localized Loss of Ca²⁺ Homeostasis in Neuronal Dendrites Is a Downstream Consequence of Metabolic Compromise during Extended NMDA Exposures

Thomas A. Vander Jagt, John A. Connor, and C. William Shuttleworth

Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131

Correspondence should be addressed to Dr. C. William Shuttleworth, Department of Neurosciences, University of New Mexico School of Medicine, MSC08 4740, 1 University of New Mexico, Albuquerque, NM 87131. Email: bshuttleworth{at}salud.unm.edu

Excessive Ca²⁺ loading is central to most hypotheses of excitotoxic neuronal damage. We examined dendritic Ca²⁺ signals in single CA1 neurons, injected with fluorescent indicators, after extended exposures to a low concentration of NMDA (5 µM). As shown previously, NMDA produces an initial transient Ca²⁺ elevation of several micromolar, followed by recovery to submicromolar levels. Then after a delay of 20–40 min, a large Ca²⁺ elevation appears in apical dendrites and propagates to the soma. We show here that this large delayed Ca²⁺ increase is required for ultimate loss of membrane integrity. However, transient removal of extracellular Ca²⁺ for varying epochs before and after NMDA exposure does not delay the propagation of these events. In contrast to compound Ca²⁺ elevations, intracellular Na⁺ elevations are monophasic and were promptly reversed by the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]. MK-801 applied after the transient Ca²⁺ elevations blocked the delayed propagating Ca²⁺ increase. Even if applied after the propagating response was visualized, MK-801 restored resting Ca²⁺ levels. Propagating Ca²⁺ increases in dendrites were delayed or prevented by (1) reducing extracellular Na⁺, (2) injecting ATP together with the Ca²⁺ indicator, or (3) provision of exogenous pyruvate. These results show that extended NMDA exposure initiates degenerative signaling generally in apical dendrites. Although very high Ca²⁺ levels can report the progression of these responses, Ca²⁺ itself may not be required for the propagation of degenerative signaling along dendrites. In contrast, metabolic consequences of sustained Na⁺ elevations may lead to failure of ionic homeostasis in dendrites and precede Ca²⁺-dependent cellular compromise.

Key words: excitotoxicity; CA1; hippocampus; sodium ion; ATP; MK-801; brain slice

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Received July 3, 2007; revised March 17, 2008; accepted March 24, 2008.

Correspondence should be addressed to Dr. C. William Shuttleworth, Department of Neurosciences, University of New Mexico School of Medicine, MSC08 4740, 1 University of New Mexico, Albuquerque, NM 87131. Email: bshuttleworth{at}salud.unm.edu

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