Unveiling glial pathways involved in neuronal communication
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Glia have been understudied throughout time largely because of a lack of basic understanding. Early experiments showing that glia do not respond with action potentials after an electrical stimulation, like their neuronal counterparts did, greatly reduced the scope for studying glia. Now, we understand glia enough to know they respond to neurons and can influence their firing patterns. There is a lot of controversy in the details behind how glia influence neuronal activity, some groups have evidence for glio-transmission, while other groups have evidence against glio-transmission. The major discrepancies between these two hypotheses come from the use of improper controls. A stronger comprehension of basic glio-biology should reduce our ignorance and allow us to better address the questions. Neither group denies glia's ability to modulate neuronal activity, so there still exists a niche for greater genetic understanding of how glia communicate with neurons. The Drosophila model organism is an excellent model for gaining genetic insight onto basic glio-biology. The overall goal of this dissertation was to identify glial genes which modify neuronal activity. To accomplish this, I took advantage of the TRPA1-induced paralysis behavior and the genetic prowess of Drosophila forward genetic modifier screens to identify glial genes that modify neuronal activity. Then I conducted secondary genetic screens to identify glial subsets which utilized the candidate genes identified from the first screen. Chapter 1 lays out the general background information built on which I conducted my dissertation research. In chapter 2, I delve into specific modifiers I identified using the forward genetic screen. I find evidence that glia utilize transporters and a calcium- and SNARE-dependent mechanism to alter neuronal activity. We rationalized that despite artificial glial activation through ectopic TRPA1 expression, our data provide supporting evidence for glio-transmission. In chapter 3, I delve into the genetic complexities observed including gender differences and the broad category of genetic modifiers tested. I found strong gender differences male and female flies particularly when the modifiers were SNARE- or ion-related, and a unique biphasic temperature-dependent response in the paralysis behavior. In addition, we found evidence for gap junction modulation of the TRPA1-induced paralysis behavior. From the secondary screen, I identified the ensheathing glial subset driver NP6520-GAL4 phenocopied our results from primary screen which utilized Repo-GAL4, concluding that this subset forms tripartite synapses with a glutamate-inhibitory neuron synapse. Lastly, chapter 4 finishes up with conclusions and sets up hypotheses to be tested in the future. Overall, further glial studies are needed to fully elucidate glial interactions with neurons.
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Ph. D.