The Role Of Astrocytes In The Development Of Central Chemosensitivity

Authors

Kelsey Patterson, University of Alabama at Birmingham

Advisory Committee Chair

Michelle L Olsen

Advisory Committee Members

John J Hablitz

Robin G Lorenz

Alan K Percy

David G Standaert

Jacques Wadiche

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In the two decades since MECP2 was identified as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this X-linked neurodevelopmental disease. However, their exclusive use presents a limitation in translating findings from animal models to the clinic. Here, we characterized growth, anatomical, behavioral, and motor deficits in a novel zinc-finger nuclease murine RTT model from birth through adulthood. Male rats lacking the transcriptional regulatory protein, MeCP2 (Mecp2ZFN/y), are noticeably symptomatic as early as postnatal day (P) 21 and die prematurely, while females lacking one copy of Mecp2 (Mecp2ZFN/+) show a protracted disease course. Rats of both sexes recapitulate many key mouse and human RTT phenotypes, including baseline respiratory abnormalities. Although RTT is primarily considered a neuronal disease, recent studies implicate other cell types, including astrocytes, in the pathogenesis of such respiratory deficits. Evidence from normal neurophysiology indicates that astrocytes in the retrotrapezoid nucleus (RTN) act as chemosensors (CO2/H+ sensors) to regulate breathing, though the mechanism by which this occurs remains unclear. Astrocytes are mediators of K+ ion and glutamate homeostasis, and proteins conferring these functions, such as the inwardly-rectifying K+ channel Kir4.1, are upregulated during early postnatal development in parallel with MeCP2 expression. The gene encoding Kir4.1 is a reported target of MeCP2, and Kir4.1 protein is downregulated in RTT mice, suggesting that aberrant Kir4.1 expression in RTN astrocytes may contribute to RTT respiratory deficits. To first establish the role of Kir4.1 in normal chemoreception, we performed electrophysiology in rat RTN and cortex during the first two postnatal week of life. We found that Kir4.1-mediated chemoreception is unique to RTN astrocytes and developmentally upregulated in parallel with brainstem Kir4.1 and Kir5.1 expression. Pharmacologic Kir4.1 modulation is sufficient to increase RTN neuronal firing, suggesting that Kir4.1 disruption represents a candidate means by which central chemosensitivity is impaired early in RTT development. Translating these findings from the context of normal postnatal neurodevelopment to the RTT rat model offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies.

Recommended Citation

Patterson, Kelsey, "The Role Of Astrocytes In The Development Of Central Chemosensitivity" (2018). All ETDs from UAB. 2683.
https://digitalcommons.library.uab.edu/etd-collection/2683