Overexpression of a Shaker-type potassium channel in mammalian central nervous system dysregulates native potassium channel gene expression.
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.
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
M L
ML
Sutherland
S H
SH
Williams
R
R
Abedi
P A
PA
Overbeek
P J
PJ
Pfaffinger
J L
JL
Noebels
D000818:Animals; D001921:Brain / Q000502:physiology*; D002540:Cerebral Cortex / Q000502:physiology; D018891:Dentate Gyrus / Q000502:physiology; D004569:Electroencephalography; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000378:metabolism; D051637:Shaker Superfamily of Potassium Channels; D014158:Transcription, Genetic
D015221:Potassium Channels; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051637:Shaker Superfamily of Potassium Channels