2013 — 2019 |
Mosca, Timothy James |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
The Development and Organization of Central Synapses in Drosophila
DESCRIPTION (provided by applicant): All aspects of memory, behavior, and cognition rely on the synaptic connections between neurons. To begin to understand neural function, the synapses themselves must first be understood: how are they organized, what are the molecular mechanisms necessary for their development and function, and how do synapses from one type of neuron interact with the synapses from other neuronal classes? This proposal aims to address these questions by determining the organization of synapses in the central brain of Drosophila melanogaster, the molecules necessary for their maintenance and development, and how synapses of different neurons interact. In the Drosophila olfactory system, three neuronal classes cooperate to enable robust sensing of odors from the environment, processing of these odors, and transmission of the information to higher brain centers. The olfactory system thus represents an opportunity to study a genetically accessible system with single-cell resolution and stereotypy within single neurons or between groups of neurons. I have developed methods to study synapse organization in the olfactory system, establishing a new model central synapse. These methods have revealed new aspects of synaptic organization in olfactory neurons in the Drosophila antennal lobe. This proposal will further this work, providing a high-resolution analysis of synapses in single olfactory neurons. It will determine when these synapses develop and how the developing synapse differs from that of the mature olfactory neuron. Such analyses will provide an essential framework from which to address how pathological conditions, including neurodevelopmental disorders, can alter synapse organization. Further, I will use this new model synapse to examine three classes of molecules, the Teneurins, Neurexins and Neuroligins, which are linked to intellectual disabilities and autism spectrum disorders. Understanding how each of these entities contributes to synapse organization is essential for gaining insight into the bases of these disorders. Finally, I will investigate how the synapses of different neurons within a circuit are interrelated. Coordination among neurons in a circuit is essential for its function and organismal behavior. But how a circuit achieves this coordination on a synaptic level is largely unknown. Using newly established methods, I will ask how perturbing the synapses of one neuronal class within a circuit affect synapses of the other neurons. Specifically, I will determine how a circuit deals wih synapse increase and reduction in one specific type, and how chemical synapses within a circuit respond to the loss of electrical synapses. Further study of the mechanisms underlying these circuit responses will unveil new molecules and organizational paradigms responsible for their construction. By understanding these aspects of organization for individual synapses and between groups of synapses, we will gain considerable insight into not just neuronal function, but into how a neural circuit coordinates information to ensure proper function at the organism level.
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0.973 |
2019 — 2021 |
Mosca, Timothy James |
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. |
Molecular and Cellular Mechanisms That Underlie Synaptic Maturation @ Thomas Jefferson University
PROJECT SUMMARY / ABSTRACT MOLECULAR AND CELLULAR MECHANISMS THAT UNDERLIE SYNAPTIC MATURATION In all nervous systems, from invertebrates to humans, newly formed synaptic connections are not yet optimally functional. All synapses must undergo a process of synaptic maturation to transition from structurally simple and functionally unrefined connections to structurally complex connections capable of robust synaptic transmission and plasticity. This process is critically important, as failures in synaptic maturation have a marked bearing in health and disease, underlying neurodevelopmental disorders and intellectual disabilities. Recent work has even suggested that the maturation process may also be hijacked in neurodegenerative diseases like Alzheimer?s. Despite this importance, the molecular mechanisms that underlie synaptic maturation remain poorly understood. Structural events including the recruitment of postsynaptic proteins to nascent presynaptic terminals must preface functional maturation, but even our understanding of the genes and pathways that enable these events remains incomplete. Specifically, the presynaptic receptors involved in maturation remain woefully understudied and there are still critical gaps in our understanding of how established maturation signals are processed postsynaptically to promote development. The long-term goal of this proposal is to identify the molecules that ensure normal synaptic maturation and determine the mechanisms by which they function. To understand these fundamental events, we will combine genetic, high-resolution imaging, and biochemical approaches to investigate the mechanisms that underlie synaptic maturation. Our preliminary work has identified three transmembrane proteins that likely function in structural synaptic maturation. Two such proteins are essential for the normal function and expression of ?-secretase, a protein complex that normally cleaves amyloid precursor protein into A?, and whose dysfunction is linked to familial, early-onset Alzheimer?s disease. These proteins are also involved in neuronal differentiation, underscoring their importance in a normally functioning nervous system. The third protein represents a novel transmembrane receptor. We will first characterize how each of these molecules contribute to synaptic growth and maturation. Following, we will determine where these genes are expressed and whether they function presynaptically or postsynaptically to mediate synaptic maturation. Finally, we will begin to determine the mechanism by which these genes function and intersect with established signaling pathways that regulate synaptic maturation and development. We expect that this work will first identify new genes that function pre- and postsynaptically to ensure synaptic maturation and second, the mechanisms by which they achieve this goal. With a deeper understanding of the normal function of these genes, we can better understand how they work to stave off disorders like Alzheimer?s disease when present and how mutations in those genes can contribute to the progression of neurodegenerative diseases. In so doing, we will establish a fundamental foundation for the cellular events underlying maturation and begin to inform how impaired synaptic maturation can underlie neurodevelopmental disorders, intellectual disabilities, and neurodegenerative diseases.
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0.965 |