Date of Award

Fall 2021

Project Type

Dissertation

Program or Major

Genetics

Degree Name

Doctor of Philosophy

First Advisor

Xuanmao Chen

Second Advisor

Kelley W Thomas

Third Advisor

David Plachetzki

Abstract

The primary cilium is a unique cellular organelle that emanates from the mother centriole and extends out of the plasma membrane of nearly every mammalian cell. While originally believed to be a vestigial appendage, the cilium is now known to be a signaling hub where various intercellular communication pathways intersect to regulate morphogenesis, proliferation, polarity, differentiation, and homeostasis. Due to their importance in regulating cellular functions the cilium has become a growing focus of biomedical research as it has been linked to at least 35 human developmental disorders which have been termed ciliopathies. In the nervous system, primary cilia regulate many neuronal functions including sensory perception, energy balance, neurodevelopment, and adult neurogenesis. In recent years ciliary genes have been implicated in major depressive disorder, autism spectrum disorder Alzheimer’s disease, and Parkinsons disease. Although the mechanisms of action of primary cilia in these afflictions are not yet fully understood, they are strongly implicated in human health and are emerging as a potential drug targets to develop novel treatments for individuals suffering from these diseases. In this study I first examined the cause of neonatal death in a transgenic mouse model for major depressive disorder (MDD) where the ciliary gene AC3 was conventionally knocked out to assess its validity in developmental and depression research. I found that the cause of death was anosmia-induced starvation and was not caused developmental defects. I next evaluated the impact of selective serotonin reuptake inhibitors (SSRIs) on cilia morphology to determine if neuronal primary cilia are a previously undocumented target of anti-depressant treatments. I found that neuronal primary cilia are sensitive to some SSRIs as well as other medications, and that these drugs can significantly alter cilia length. I also investigated the impact that knocking-out IFT88, a gene essential for ciliogenesis, has on sleep patterning and cortical EEG activity. I found that ablation of primary cilia (in the IFT88 KO mice) disrupts sleep cycles, reduces power of the EEG waveform, and impairs theta-gamma phase-amplitude coupling.

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