SIK3 & Wnk signals through Fray to regulate glial K+ buffering and seizure susceptibility in Drosophila models of hyperexcitability
Date of Award
Doctor of Philosophy (PhD)
K+ homeostasis is important for maintaining healthy, physiological levels of neuronal activity. Glial cells play a central role in maintaining homeostatic ion gradients. In previous work from our lab, we unravel a glial K+ buffering program that is centered on a key kinase, salt-inducible kinase 3 (SIK3). SIK3-HDAC4 signaling in glial regulates the transcription of channels and transporters involved in water and ion transport. Defects in this pathway lead to peripheral nerve edema, neuronal hyperactivity, and seizure sensitivity. In an hyperexcitability mutant, eag Shaker, we show this pathway is downregulated and genetic activation suppresses seizure behavior. In this thesis, I describe two signaling pathways, SIK3 and Wnk, that converge onto Fray to regulate glial K+ buffering. Bypassing SIK3 and Wnk regulation, I show that a constitutively active Fray is sufficient to suppress seizure phenotypes in three molecularly distinct models of hyperexcitability. Additionally, I identify cortex glia as a critical glial subtype for seizure behavior. Taken together, this work highlights the therapeutic potential of enhancing K+ buffering to treat diseases of hyperexcitability.
Chair and Committee
Lones, Lorenzo Laronn, "SIK3 & Wnk signals through Fray to regulate glial K+ buffering and seizure susceptibility in Drosophila models of hyperexcitability" (2022). Arts & Sciences Electronic Theses and Dissertations. 2744.