The neurogenetic analysis of synaptogenesis and synaptic plasticity in Drosophila melanogaster
Item
-
Title
-
The neurogenetic analysis of synaptogenesis and synaptic plasticity in Drosophila melanogaster
-
Identifier
-
d_2009_2013:76f0034c1990:11392
-
identifier
-
11682
-
Creator
-
Wise, Alexandria Augustine,
-
Contributor
-
Tadmiri Venkatesh
-
Date
-
2012
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Molecular biology | Neurosciences | Anaphase Promoting Complex/Cyclosome | Drosophila A kinase anchoring protein (DAKAP) | plasticity | Retina aberrant in pattern/Fizzy related | synaptic transmission | synaptogenesis
-
Abstract
-
Synaptogenesis is the process by which nascent axons from developing neurons target and form mature synapses with other neurons or cells. Specifically, synaptogenesis at the neuromuscular junction (NMJ) involves the motorneuron axon targeting its specific innervating muscle. The NMJ of the Drosophila larva is an excellent model system to study synaptogenesis due to genetic tools developed in the Drosophila melanogaster. The NMJ in Drosophila are glutamatergic, resembling mammalian central nervous system (CNS) excitatory synapse, and can provide insight into the molecular mechanisms that control synapse development and transmission. In addition, studying the physiology of the synapse can also provide for greater understanding of mechanisms that underlie synapse maintenance and plasticity.;In this dissertation, I have focused on the role of two functionally dynamic pathways, ubiquitination and cAMP-PKA (protein kinase A or A kinase) during development, and their role in NMJ synaptic structure and function. rugose (rg), which encodes for the Drosophila A kinase anchoring protein 550 (DAKAP550), belongs to a family of cAMP-PKA organizing centers that provide the scaffolding to permit PKA to bind to specific subcellular organelles, allowing for cAMP to activate PKA more effectively. There were changes observed in hypomorphic rg mutants in synaptic transmission and plasticity as well as in basic forms of learning, specifically habituation, which involves the neuron, in this case, to cease responding to presented stimuli. Taken together, rg is necessary for the development of the synapse and synaptic transmission.;Our lab has previously shown that Retina aberrant in pattern/Fizzy related (Rap/Fzr), the activating subunit of the, E3 ubiquitin ligase, Anaphase Promoting Complex (APC/C) regulates cell fate determination in the developing Drosophila brain. Our cell biological, ultrastructural, electrophysiological, and behavioral data show that rap/fzr loss-of-function mutations lead to changes in synaptic structure and function, as well as locomotion defects. Specifically these changes were observed pre- and postsynaptically, represented by size and morphology of synaptic boutons, and number of neurotransmitter vesicles. Electrophysiologically, these were correlated with decreased transmission failure rates as well as increase in the size of synaptic potentials. In addition, larval locomotion and peristaltic movement are also impaired as. These findings suggest a novel role for Drosophila-Cdh1-mediated ubiquitination during development of functional synapses in the peripheral nervous system.;The use of genetic modifier screens in our laboratory has identified several neuronal substrates that physically interact with APC/CCdh1/Rap/Fzr in Drosophila. As a part of my thesis research, I focused on three proteins: Locomotion Defects (Loco), Nonstop (Not) and Twins. Their involvement in signaling pathways makes these proteins candidates together with Rap/Fzr/Cdh1 to regulate synaptogenesis at the pre- and postsynapse of the Drosophila NMJ. This data suggest Not, Loco and Twins are localized at the NMJ, and involved in regulating synaptic development by genetically interacting with APC/CCdh1/Rap/Fzr.;Both of these pathways play an important role in neuronal development, transmission, learning and memory, and dysfunction. However, their role in modifying synaptic activity remains unclear. Using Drosophila melanogaster as a model, this thesis will elucidate the role of the APC/C and Rugose in synaptic development and plasticity at the neuromuscular junction.
-
Type
-
dissertation
-
Source
-
2009_2013.csv
-
degree
-
Ph.D.
-
Program
-
Biology
