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The Journal of Neurophysiology Vol. 83 No. 2 February 2000, pp. 735-745
Copyright ©2000 by the American Physiological Society
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710
Müller, Michael and
George G. Somjen.
Na+ and K+ Concentrations, Extra- and
Intracellular Voltages, and the Effect of TTX in Hypoxic Rat
Hippocampal Slices. J. Neurophysiol. 83: 735-745, 2000. Severe hypoxia causes rapid depolarization
of CA1 neurons and glial cells that resembles spreading depression
(SD). In brain slices in vitro, the SD-like depolarization and the
associated irreversible loss of function can be postponed, but not
prevented, by blockade of Na+ currents by tetrodotoxin
(TTX). To investigate the role of Na+ flux, we made
recordings from the CA1 region in hippocampal slices in the presence
and absence of TTX. We measured membrane changes in single CA1
pyramidal neurons simultaneously with extracellular DC potential
(Vo) and either extracellular
[K+] or [Na+]; alternatively, we
simultaneously recorded [Na+]o,
[K+]o, and Vo.
Confirming previous reports, early during hypoxia, before SD onset,
[K+]o began to rise, whereas
[Na+]o still remained normal and
Vo showed a slight, gradual, negative shift;
neurons first hyperpolarized and then began to gradually depolarize.
The SD-like abrupt negative 
Vo
corresponded to a near complete depolarization of pyramidal neurons and
an 89% decrease in input resistance. [K+]o
increased by 47 mM and [Na+]o dropped by 91 mM. Changes in intracellular Na+ and K+
concentrations, estimated on the basis of the measured extracellular ion levels and the relative volume fractions of the neuronal, glial,
and extracellular compartment, were much more moderate. Because
[Na+]o dropped more than
[K+]o increased, simple exchange of
Na+ for K+ cannot account for these ionic
changes. The apparent imbalance of charge could be made up by
Cl
influx into neurons paralleling Na+ flux
and release of Mg2+ from cells. The hypoxia-induced changes
in interneurons resembled those observed in pyramidal neurons.
Astrocytes responded with an initial slow depolarization as
[K+]o rose. It was followed by a rapid but
incomplete depolarization as soon as SD occurred, which could be
accounted for by the reduced ratio,
[K+]i/[K+]o. TTX (1 µM) markedly postponed SD, but the SD-related changes in
[K+]o and [Na+]o
were only reduced by 23 and 12%, respectively. In TTX-treated pyramidal neurons, the delayed SD-like depolarization took off from a
more positive level, but the final depolarized intracellular potential
and input resistance were not different from control. We conclude that
TTX-sensitive channels mediate only a fraction of the Na+
influx, and that some of the K+ is released in exchange for
Na+. Even though TTX-sensitive Na+ currents are
not essential for the self-regenerative membrane changes during hypoxic
SD, in control solutions their activation may trigger the transition
from gradual to rapid depolarization of neurons, thereby synchronizing
the SD-like event.
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