Sutherland M L, Williams S H, Abedi R, Overbeek P A, Pfaffinger P J, Noebels J L
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2451-5. doi: 10.1073/pnas.96.5.2451.
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.
神经系统维持兴奋与抑制之间的微妙平衡，部分是通过电压门控钠通道和钾离子通道之间复杂的相互作用来实现的。由于钾通道阻断或基因缺失会导致过度兴奋，因此一般认为钾通道基因表达的增加应会降低神经网络的兴奋性。我们通过创建一种表达Shaker型钾通道基因的转基因小鼠来验证这一假设。矛盾的是，我们发现额外的钾通道基因的添加导致了过度兴奋而非低兴奋性的表型。转基因的存在导致成年中枢神经系统中内源性Shaker基因的复杂失调，以及网络兴奋性的增加，这包括自发的皮层棘波和波发放，以及孤立海马切片中癫痫样爆发的阈值降低。这些数据表明，钾通道基因剂量的增加会导致正常钾通道基因表达的失调，并且它可能是导致人类非整倍体疾病（如唐氏综合征）发病机制的一种潜在机制。
