SIK3 suppresses neuronal hyperexcitability by regulating the glial capacity to buffer K⁺ and water

Glial regulation of extracellular potassium (K⁺) helps to maintain appropriate levels of neuronal excitability. While channels and transporters mediating K⁺ and water transport are known, little is understood about upstream regulatory mechanisms controlling the glial capacity to buffer K⁺ and osmotically obliged water. Here we identify salt-inducible kinase 3 (SIK3) as the central node in a signal transduction pathway controlling glial K⁺ and water homeostasis in Drosophila. Loss of SIK3 leads to dramatic extracellular fluid accumulation in nerves, neuronal hyperexcitability, and seizures. SIK3-dependent phenotypes are exacerbated by K⁺ stress. SIK3 promotes the cytosolic localization of HDAC4, thereby relieving inhibition of Mef2-dependent transcription of K⁺ and water transport molecules. This transcriptional program controls the glial capacity to regulate K⁺ and water homeostasis and modulate neuronal excitability. We identify HDAC4 as a candidate therapeutic target in this pathway, whose inhibition can enhance the K⁺ buffering capacity of glia, which may be useful in diseases of dysregulated K⁺ homeostasis and hyperexcitability.