Overexpression of a Shaker-type potassium channel in mammalian central nervous system dysregulates native potassium channel gene expression
- M. L. Sutherland*†,
- S. H. Williams*†,
- R. Abedi*,
- P. A. Overbeek†‡§,
- P. J. Pfaffinger†, and
- J. L. Noebels*†§¶
- *Department of Neurology, †Division of Neuroscience, §Department of Molecular and Human Genetics, and ‡Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030
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Edited by Richard L. Sidman, Harvard Medical School, Southborough, MA, and approved December 31, 1998 (received for review October 22, 1998)
Abstract
The nervous system maintains a delicate balance between excitation and inhibition, partly through the complex interplay between voltage-gated sodium and potassium ion channels. Because K+ channel blockade or gene deletion causes hyperexcitability, it is generally assumed that increases in K+ channel gene expression should reduce neuronal network excitability. We have tested this hypothesis by creating a transgenic mouse that expresses a Shaker-type K+ channel gene. Paradoxically, we find that addition of the extra K+ channel gene results in a hyperexcitable rather than a hypoexcitable phenotype. The presence of the transgene leads to a complex deregulation of endogenous Shaker genes in the adult central nervous system as well as an increase in network excitability that includes spontaneous cortical spike and wave discharges and a lower threshold for epileptiform bursting in isolated hippocampal slices. These data suggest that an increase in K+ channel gene dosage leads to dysregulation of normal K+ channel gene expression, and it may underlie a mechanism contributing to the pathogenesis of human aneuploidies such as Down syndrome.
Footnotes
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↵¶ To whom reprint requests should be addressed at: Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. e-mail: jnoebels{at}bcm.tmc.edu.
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This paper was submitted directly (Track II) to the Proceedings Office.
ABBREVIATIONS
- CNS,
- central nervous system;
- HypK,
- hyperexpressing K+ channel;
- HPRT,
- hypoxanthine phosphoribosyltransferase;
- HSV,
- herpes simplex virus;
- [K+]ext,
- extracellular potassium concentration
- Received October 22, 1998.
- Copyright © 1999, The National Academy of Sciences
