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 5-15-2019

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

Synaptic development is a complex and highly orchestrated process in which the nervous system must build appropriately sized and sufficiently strong connections between neurons and their targets. Many neurodevelopmental disorders are caused by dysregulation of the mechanisms that promote the formation of normal synaptic connections. Here, I show that dysregulation of neuronal stress pathways during development negatively impacts synaptic growth and functionality. First, I explore the Drosophila model of Fragile X Syndrome, a common and debilitating disorder that causes intellectual disability and autism spectrum disorders in humans. I show that chronic, excess signaling through the Wallenda/DLK stress pathway drives synaptic dysfunction, circuit dysregulation, and abnormal behaviors. Second, I show that the NAD+ synthesizing enzyme, dNmnat, which is an axoprotective factor, must be degraded at the synapse to promote synaptic transmission at the developing larval neuromuscular junction. In total, this work shows that the pathways that govern neuronal stress responses must be downregulated during development to promote normal nervous system function. This highlights a new paradigm in which to consider neurodevelopmental disorders: chronic upregulation of stress pathways may contribute to the lifelong symptoms associated with these disorders. This implies that not all neuronal dysfunction is permanently set during development. Thus, there is hope for the application of therapies in neurodevelopmental disorders that target active signaling through neuronal stress pathways.

Language

English (en)

Chair and Committee

Aaron DiAntonio

Committee Members

Yehuda Ben-Shahar, Erik Herzog, Valeria Cavalli, Joseph Dougherty,

Comments

Permanent URL: https://doi.org/10.7936/hszt-5t49

Available for download on Monday, May 15, 2119

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