Basic Science

Abstract

Abstract Laura A. Jansen, Erik J. Uhlmann, Peter B. Crino, David H. Gutmann, and Michael Wong Individuals with Tuberous Sclerosis Complex (TSC) frequently suffer from intractable epilepsy. To gain insight into the causes of epilepsy in TSC, we previously developed a mouse model of TSC with inactivation of the Tsc1 gene selectively in brain astrocytes (Tsc1GFAPCKO mice). Astrocytes, the main category of glial cells in brain, are important supporting cells in the brain, and also have direct effects on brain physiology, development, and repair. These mice develop progressive seizures, suggesting that astrocyte dysfunction may be involved in the development of epilepsy in TSC. Since one of the important functions of astrocytes is to limit sudden elevations of extracellular potassium in the brain, which would lead to neuronal excitability, in this study we investigated the hypothesis that impairment of potassium uptake may contribute to the development of seizures in Tsc1GFAPCKO mice. Astrocytes take up potassium from the extracellular space via a membrane channel, called the Kir channel. Cultured astrocytes from Tsc1GFAPCKO mice exhibited reduced Kir potassium currents and decreased expression of specific Kir channel protein subunits. mRNA expression of the same Kir subunits was also reduced in astrocytes from Tsc1GFAPCKO mice. Furthermore, we showed that the impairment in Kir channel function was reversed with drugs (roscovitine and retinoic acid) that modulate cell signaling pathways implicated in TSC. Lastly, hippocampal slices from Tsc1GFAPCKO mice exhibited decreased astrocytic Kir currents, as well as increased susceptibility to potassium-induced seizure-like activity. In conclusion, impaired extracellular potassium uptake by astrocytes through Kir channels may contribute to increased neuronal excitability and the development of epilepsy in a mouse model of TSC.