We will analyze the actions of genes that regulate how photoreceptor synapses in Drosophila form and function, and how these contribute to circuits of neurons in the fly's visual system. Projects focus on the photoreceptor target interneuron in the first and second neuropils, the lamina and medulla, functional counterparts to the outer and inner plexiform layers of the retina. A long-term objective is to understand the organization of multiple-contact synapses (such as dyads and triads) from the fly's photoreceptor tetrad synapses. More recent objectives are to understand how these form and then contribute to the visual system's synaptic microcircuits. Current objectives are to study axon targeting prior to photoreceptor synaptogenesis, and the action of crumbs in directing growth cone trajectories. The numbers and types of feedback photoreceptor synapses will be studied using genetic reagents to label and identify participating neurons at EM level, and the involvement of Kirre and Irrec-like proteins as well as Dscam cell adhesion molecules in establishing the specificity of synapses between two types of lamina feedback interneuron, L2 and L4, as well as in regulating reciprocity between these. The projects use mutants and knockdowns of the corresponding genes, and other genetic reagents. Synaptic function will be examined from mutants that alter the synaptic vesicle phenotype of photoreceptors, or the targeting of their terminals, as well as the recycling of neurotransmitter, histamine, through a beta-alanyl conjugation pathway. Pathway strength for photoreceptor feedback will be evaluated from synapse numbers in different mutant backgrounds to reveal the network regulation of synaptic circuits. These projects examine mutant photoreceptors using advanced methods of serial-section and immuno-EM, and skilled personnel to implement these. Analysis of synaptic circuits in the complex medulla will continue, using serial-EM to identify actual circuits between identified neurons of the pathways underlying spectral discrimination. These data will be used to examine the neural basis of color vision;to identify circuit design and the frequencies of network motifs in synaptic circuits;and to examine the regulation that these undergo in both the lamina and medulla when contributing neurons are eliminated or genetically transformed. The proposed studies will identify the cellular mechanisms for synaptic function and organization in visual systems, and the rearrangements these undergo in functional and disease states of the retina, and will be identified from their genetic bases in a model visual system with marked similarities to the retina.

Public Health Relevance

The studies aim to produce a basic model of synaptogenesis applicable to polyadic synapses like the retina's dyads and triads, and identify underlying genetic bases for changes that result from congenital or dystrophic diseases, or retinal damage, and the regulation of the retina's synaptic networks. The projects analyze how anatomical synaptic circuits, many with counterparts in the retina, give rise to modules of visual behavior.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
4R01EY003592-33
Application #
8448536
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
1981-02-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
33
Fiscal Year
2013
Total Cost
$184,290
Indirect Cost
$13,651
Name
Dalhousie University
Department
Type
DUNS #
207799404
City
Halifax, Nova Scotia
State
NS
Country
Canada
Zip Code
B3 4-R2
Schwabe, Tina; Borycz, Jolanta A; Meinertzhagen, Ian A et al. (2014) Differential adhesion determines the organization of synaptic fascicles in the Drosophila visual system. Curr Biol 24:1304-13
Lüthy, Kevin; Ahrens, Birgit; Rawal, Shilpa et al. (2014) The irre cell recognition module (IRM) protein Kirre is required to form the reciprocal synaptic network of L4 neurons in the Drosophila lamina. J Neurogenet 28:291-301
Shinomiya, Kazunori; Karuppudurai, Thangavel; Lin, Tzu-Yang et al. (2014) Candidate neural substrates for off-edge motion detection in Drosophila. Curr Biol 24:1062-70
Haberman, Adam; Williamson, W Ryan; Epstein, Daniel et al. (2012) The synaptic vesicle SNARE neuronal Synaptobrevin promotes endolysosomal degradation and prevents neurodegeneration. J Cell Biol 196:261-76
Edwards, Tara N; Nuschke, Andrea C; Nern, Aljoscha et al. (2012) Organization and metamorphosis of glia in the Drosophila visual system. J Comp Neurol 520:2067-85
Borycz, Janusz; Borycz, Jolanta A; Edwards, Tara N et al. (2012) The metabolism of histamine in the Drosophila optic lobe involves an ommatidial pathway: ýý-alanine recycles through the retina. J Exp Biol 215:1399-411
Takemura, Shin-ya; Karuppudurai, Thangavel; Ting, Chun-Yuan et al. (2011) Cholinergic circuits integrate neighboring visual signals in a Drosophila motion detection pathway. Curr Biol 21:2077-84
Millard, S Sean; Lu, Zhiyuan; Zipursky, S Lawrence et al. (2010) Drosophila dscam proteins regulate postsynaptic specificity at multiple-contact synapses. Neuron 67:761-8
Hamanaka, Yoshitaka; Park, Dongkook; Yin, Ping et al. (2010) Transcriptional orchestration of the regulated secretory pathway in neurons by the bHLH protein DIMM. Curr Biol 20:9-18
Higashi-Kovtun, Misao E; Mosca, Timothy J; Dickman, Dion K et al. (2010) Importin-beta11 regulates synaptic phosphorylated mothers against decapentaplegic, and thereby influences synaptic development and function at the Drosophila neuromuscular junction. J Neurosci 30:5253-68

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