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dc.contributor.advisor Stern, Michael
dc.creatorHowlett, Eric Lane
dc.date.accessioned 2018-12-03T18:32:31Z
dc.date.available 2018-12-03T18:32:31Z
dc.date.issued 2009
dc.identifier.urihttps://hdl.handle.net/1911/103677
dc.description.abstract Use-dependent downregulation of neuronal activity (negative feedback) can act as a homeostatic mechanism to maintain neuronal activity at a particular specified value. Disruption of this negative feedback might lead to neurological pathologies such as epilepsy, but the precise mechanisms by which this feedback can occur remain incompletely understood. At one glutamatergic synapse, the Drosophila neuromuscular junction, a mutation in the group II metabotropic glutamate receptor gene ( DmGluRA ) increased motor neuron excitability by disrupting an autocrine, glutamate-mediated negative feedback. I show that DmGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt, a product of PI3K signaling, within motor nerve terminals in a DmGluRA -dependent manner. Finally, I show that PI3K increases both axon diameter and synapse number via the Tor/S6 kinase pathway, but not Foxo. In humans, PI3K and group II mGluRs are implicated in epilepsy, neurofibromatosis, autism, schizophrenia and other neurological disorders; however, neither the link between group II mGluRs and PI3K, nor the role of PI3K-dependent regulation of Foxo in the control of neuronal excitability, had been previously reported. My work suggests that some of the deficits in these neurological disorders might result from disruption of glutamate-mediated homeostasis of neuronal excitability.
dc.format.extent 113 pp
dc.language.iso eng
dc.subjectNeurosciences
Genetics
Cellular biology
Biological sciences
Homeostasis
Metabotropic glutamate receptors
Negative feedback
Neuronal excitability PI3K
dc.title A PI3-kinase mediated negative feedback regulates neuronal excitability at the Drosophila neuromuscular junction
dc.identifier.digital 304986561
dc.type.genre Thesis
dc.type.material Text
thesis.degree.department Biochemistry and Cell Biology
thesis.degree.discipline Natural Sciences
thesis.degree.grantor Rice University
thesis.degree.level Doctoral
thesis.degree.name Doctor of Philosophy
dc.identifier.callno THESIS BIOCHEM. 2009 HOWLETT
dc.identifier.citation Howlett, Eric Lane. "A PI3-kinase mediated negative feedback regulates neuronal excitability at the Drosophila neuromuscular junction." (2009) Diss., Rice University. https://hdl.handle.net/1911/103677.


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