Date of Degree
Access restricted until 01/31/2020
PhD (Doctor of Philosophy)
Frank, C. Andrew
First Committee Member
Second Committee Member
Third Committee Member
Fourth Committee Member
Synapses must continuously maintain stable function in order for neuronal circuits and higher-order systems to properly function. By necessity, tight regulation of molecules necessary for appropriate neurotransmission coupled with homeostatic forms of plasticity function to stabilize synaptic output. The Drosophila melanogaster larval neuromuscular junction (NMJ) is an excellent model synapse for investigating both homeostatic synaptic plasticity (HSP) and neurotransmission machinery. At the NMJ, post-synaptic impairments to neurotransmitter sensitivity (decreased quantal size) initiate HSP. A retrograde, muscle-to-nerve signal instructs the presynaptic neuron to increase neurotransmitter release (quantal content) to compensate for the post-synaptic impairment and maintain synaptic output.
HSP can be separated into temporally distinct induction and maintenance phases, depending on the nature of the impairment. Acute blockade of glutamate receptors initiates rapid forms of HSP that restore synaptic output within minutes. Loss-of-function mutations in a gene encoding a glutamate receptor result in reduced quantal size, and as a result, expression of HSP over the lifespan of that animal. However, it is unclear whether these temporal phases are distinct processes with overlapping machinery, or whether both phases are part of a common process with temporal distinct signaling requirements. Here we show that, in addition to being molecularly distinct, the temporal phases are functionally distinct. We provide evidence that the long-term maintenance of HSP requires continuous inositol trisphosphate receptor (IP3R) and Ryanodine receptor (RyR) activities, but neither are necessary for the rapid induction phase of HSP.
In addition, we investigated how mutations associated with Familial Hemiplegic Migraine Type 1 (FHM1) impact synapse function and seizure behavior. We show that flies expressing this mutant channel are susceptible to seizures. Further, neurons expressing a transgene for cacophony containing the FHM1 mutations R192Q and S218L in the analogous locations showed significant hyper-excitability. Concurrent knockdown of the gene Multiple inositol polyphosphate phosphatase 2 (Mipp2) attenuated hyper-excitable phenotypes. Additionally, Mipp2 knockdown or LiCl treatment, both of which should attenuate downstream IP3R signaling, mitigated susceptibility to seizures in adults. Together these results contribute to our understanding both of both the pathophysiology of migraine and seizures.
Drosophila, homeostasis, neurotransmission
xiii, 135 pages
Includes bibliographical references (pages 116-119).
Copyright © 2018 Thomas David James
James, Thomas David. "Discrete IP3 signaling requirements underlie acute and chronic forms of homeostatic synaptic plasticity." PhD (Doctor of Philosophy) thesis, University of Iowa, 2018.
Available for download on Friday, January 31, 2020