1985 — 2010 |
Meinertzhagen, Ian A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Visual System Development and Synaptogenesis
Quantitative aspects of synaptogenesis in the visual system will be investigated from the number and distribution of photoreceptor synapses in the first optic neuropile of Musca. Studies will concentrate upon elucidating two major questions: 1) What are the developmental determinants of synapse number and spacing; 2) What influence has visual experience upon these determinants? Determination of synapse number will be examined amongst naturally occurring differences in innervation ratios between pre- and postsynaptic neurons and analyzed using quantitative EM sampling techniques. Synapse spacing will be analyzed at different developmental ages either from freeze-fractured presynaptic membrane or serial-EM of postsynaptic dendrites, to test the influence of one synaptic site upon synaptogenesis nearby and, consequently, to examine the relationship between synaptogenesis and dendritic morphogenesis. Using similar analyses, the effects of visual experience on synaptic population size and distribution will be examined following exposure to light and/or dark, either during development or in the adult. Qualitative aspects of synaptogenesis will examine possible altered synaptic classes formed either following laser-induced deletions of the postsynaptic neurons during development or in various mutants of Drosophila either lacking photoreceptor function or with the suspected absence of a class of feedback synapses or the suspected presence of an additional postsynaptic neuron. These will all be analyzed with quantitative- and serial-EM techniques with the aim of understanding the rules with which neurons normally combine at multiple-contact synapses (dyads, triads, etc.) from the novel combinations formed following perturbations. It is anticipated these studies will inform us about the regulation of synaptic population size, composition and distribution in visual neurons during development under eithr the influence of changes in cell number of differences in visual experience.
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2011 — 2013 |
Meinertzhagen, Ian A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Visual System Synapses and Circuits
DESCRIPTION (provided by applicant): 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.
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