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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.

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