Localized loss of Ca2+ homeostasis in neuronal dendrites is a downstream consequence of metabolic compromise during extended NMDA exposures.
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.
Vander Jagt
Thomas A
TA
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA.
Connor
John A
JA
Shuttleworth
C William
CW
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004334:Drug Administration Schedule; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage* / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D045604:Extracellular Fluid / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000008:administration & dosage* / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012964:Sodium / Q000378:metabolism; D014018:Tissue Distribution
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D012964:Sodium; D002118:Calcium