This item is under embargo and not available online per the author's request. For access information, please visit http://libanswers.wustl.edu/faq/5640.

Date of Award

Spring 5-15-2020

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Neuronal excitability is tightly coupled to the complex ionic dynamics in the nervous system. In particular, a surge in the extracellular level of potassium (K+) sets the stage for neuronal hyperexcitability and drives brain edema in conditions such as epilepsy and ischemia. Glia help maintain K+ homeostasis by taking K+ ions and water molecules into the cells. In this thesis, I describe a neuromodulatory circuit that regulates the glial capacity to buffer K+ stress. Centered on a key kinase in glia, salt-inducible kinase 3 (SIK3), I first uncover its downstream effectors that control the transcription of a K+ buffering gene program. This program is composed of a suite of K+ and water transport molecules important for glial regulation of K+ balance. Disruption of this glial pathway results in peripheral nerve edema, neuronal hyperexcitability, and seizure sensitivity. Moreover, I identify upstream signal transduction pathways that control glial K+ buffering. In response to K+ stress, octopamine signals through SIK3 to modulate the glial capacity to buffer K+, thereby linking neuronal activity to glial K+ buffering. Finally, I demonstrate that HDAC4, a central repressor of SIK3 signaling, can be effectively inhibited to suppress hyperexcitability in classic seizure models. Taken together, this work addresses a key gap of knowledge on mechanisms controlling the glial capacity to maintain K+ homeostasis and sheds light on glial-centric strategies that hold promise for treating seizures and other diseases of hyperexcitability.

Language

English (en)

Chair and Committee

Aaron DiAntonio

Committee Members

Paul Taghert, Jeffrey Milbrandt, Steven Mennerick, James Skeath,

Available for download on Wednesday, May 15, 2120

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