| Title | Localized loss of Ca2+ homeostasis in neuronal dendrites is a downstream consequence of metabolic compromise during extended NMDA exposures. | | Author(s) | Vander Jagt TA, Connor JA, Shuttleworth CW | | Institution | Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA. | | Source | J Neurosci 2008 May 7; 28(19):5029-39. | | MeSH | Animals
Calcium
Dendrites
Dizocilpine Maleate
Drug Administration Schedule
Excitatory Amino Acid Agonists
Excitatory Amino Acid Antagonists
Extracellular Fluid
Homeostasis
Intracellular Membranes
Male
Mice
N-Methylaspartate
Pyramidal Cells
Receptors, N-Methyl-D-Aspartate
Sodium
Tissue Distribution
| | Abstract | Excessive Ca(2+) loading is central to most hypotheses of excitotoxic neuronal damage. We examined dendritic Ca(2+) signals in single CA1 neurons, injected with fluorescent indicators, after extended exposures to a low concentration of NMDA (5 microM). As shown previously, NMDA produces an initial transient Ca(2+) elevation of several micromolar, followed by recovery to submicromolar levels. Then after a delay of approximately 20-40 min, a large Ca(2+) elevation appears in apical dendrites and propagates to the soma. We show here that this large delayed Ca(2+) increase is required for ultimate loss of membrane integrity. However, transient removal of extracellular Ca(2+) for varying epochs before and after NMDA exposure does not delay the propagation of these events. In contrast to compound Ca(2+) 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 Ca(2+) elevations blocked the delayed propagating Ca(2+) increase. Even if applied after the propagating response was visualized, MK-801 restored resting Ca(2+) levels. Propagating Ca(2+) increases in dendrites were delayed or prevented by (1) reducing extracellular Na(+), (2) injecting ATP together with the Ca(2+) indicator, or (3) provision of exogenous pyruvate. These results show that extended NMDA exposure initiates degenerative signaling generally in apical dendrites. Although very high Ca(2+) levels can report the progression of these responses, Ca(2+) 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 Ca(2+)-dependent cellular compromise. | | Language | eng | | Pub Type(s) | In Vitro
Journal Article
Research Support, N.I.H., Extramural
| | PubMed ID | 18463256 |
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