Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment

The potassium sodium-activated channel subtype T member 1 (<i>KCNT1</i>) gene encodes the Slack channel K_Na1.1, which is expressed in neurons throughout the brain. Gain-of-function variants in <i>KCNT1</i> are associated with a spectrum of epilepsy syndromes, and mice carrying those variants exhibit a robust phenotype similar to that observed in patients. <i>Kcnt1</i> knockout (KO) mice, however, have a normal lifespan without any epileptic phenotype. To understand the molecular differences between these two models, we conducted a comprehensive proteomic analysis of the cerebral cortices of <i>Kcnt1</i> KO and <i>Kcnt1</i>^R455H/+ mice, an animal model bearing a cytoplasmic C-terminal mutation homologous to a human R474H variant that results in EIMFS. The greatest change observed in <i>Kcnt1</i> KO mice compared to the wild-type mice was the increased expression of multiple proteins of the inner mitochondrial membrane. Electron microscopy studies of cortical mitochondria from <i>Kcnt1</i> KO mice further confirmed a significant increase in the density of mitochondrial cristae compared to that in wild-type mice. <i>Kcnt1</i> reduction by a murine-specific <i>Kcnt1</i> antisense oligonucleotide (ASO) in <i>Kcnt1</i>^R455H/+ mice partially corrected the proteomic dysregulations in the disease model. The results support the hypothesis that ASO-mediated <i>KCNT1</i> reduction could be therapeutically useful in the treatment of <i>KCNT1</i> epilepsies.