ORCID ID

0000-0002-4831-1639

Publication Date

2022-04-29

Document Type

Doctoral Dissertation

Academic Program

MD/PhD

Department

Department of Neurobiology; Schafer Lab

First Thesis Advisor

Dorothy P. Schafer

Keywords

microglia, TNF-α, IRF8, cytokines, neural-immune interactions, seizures, synapses

Abstract

Microglia are the resident macrophage in the central nervous system (CNS) that actively survey their environment and participate in shaping neuronal circuits. Among the transcription factors necessary for microglia development, interferon regulatory factor 8 (IRF8) is a known risk gene for multiple sclerosis and lupus and it has recently been shown to be downregulated in schizophrenia. These studies suggest that lack of microglial IRF8 can subsequently impact neuronal function in disease, but the mechanisms underlying these effects remain unknown. While most studies have focused on IRF8-dependent regulation of immune cell function, little is known about how it impacts neural circuits. To interrogate the impact of disrupted microglial IRF8 signaling on brain circuits, I first show by RNAseq that several genes known to regulate neuronal function are dysregulated basally in Irf8-/- brains. I then found that these molecular changes are reflected in heightened neural excitability and a profound increase in susceptibility to chemically-induced lethal seizures in Irf8-/- mice. Importantly, I also show that developmental synaptic pruning, a key function for microglia, proceeds normally in Irf8-/-mice. Finally, I identified that these IRF8-dependent effects on circuits are due to elevated TNF-α in the CNS as genetic or acute pharmacological blockade of TNF-α in the Irf8-/- CNS rescued the seizure phenotype. These results provide important insights into the consequences of IRF8 signaling and TNF-α on neural circuits. The next steps are to use cell-specific genetic approaches to manipulate this signaling, which I have further developed over the course of this project.

DOI

10.13028/1y3s-tf22

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Available for download on Friday, June 14, 2024

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