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

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Abstract
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.

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