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Date of Award
Doctor of Philosophy (PhD)
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.
Chair and Committee
Yehuda Ben-Shahar, Erik Herzog, Valeria Cavalli, Joseph Dougherty,
Russo, Alexandra, "Neuronal stress pathways influence synaptic development and nervous system function in Drosophila melanogaster" (2019). Arts & Sciences Electronic Theses and Dissertations. 1831.
Available for download on Monday, May 15, 2119