The proper formation of neural circuits is critical for fundamental processes, such as perception, thought, and behavior. While much is known about the molecules that promote synaptogenesis, far less is known about the molecular pathways that negatively regulate this process. The use of genetic model organisms may accelerate the discovery of molecules required for this process, as large-scale gene discovery techniques are feasible. We propose to take an innovative approach to studying synaptic regulation by investigating a defined neural circuit at multiple levels. We will assay behavioral output at the highest level, specific synaptic connections between the neurons utilizing the trans-synaptic split-GFP based marker NLG-1 GRASP, and the individual molecules required for these events using molecular and genetic manipulations. This proposal is relevant to the NINDS mission to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. Using this approach, we have discovered that Fibroblast Growth Factor (FGF) is required to downregulate synaptogenesis within a defined sensory circuit. In addition, we have discovered that a Receptor Protein Tyrosine Phosphatase (RPTP) is required to promote synaptogenesis within this circuit. Our research will characterize the pathways that transduce the FGF signal, and the means by which these two conserved pathways interact to regulate synaptogenesis.
Our specific aims are to: 1) elucidate the pathway by which the FGF signal regulates synaptogenesis, and 2) determine how the FGF and RPTP pathways interact to mediate synaptogenesis. The robust prior characterization of this circuit, in combination with the powerful tools we have to study them, offers the unique potential to discover new and unexpected signaling pathways that negatively regulate synaptogenesis during neural circuit formation, which can then be explored in other systems. FGFs and their receptors have been linked to epilepsy, schizophrenia, bipolar disorder and depression, so understanding this new role for FGF in neural circuit formation may inform our understanding of these disorders. This R15 will fund the research of approximately 18 undergraduates and 3 M.S. students over three years, including many minority trainees at San Jos State University (SJSU), a primarily undergraduate and Masters-level university committed to training under-represented minority students. Undergraduates will perform the majority of the proposed work, with training and mentorship from M.S. students, a technician, and the PI. This funding would allow the PI to continue to develop a strong track record in research, give meaningful research experiences to undergraduate students, and strengthen the research environment at SJSU.

Public Health Relevance

During development, the formation of synaptic connections between neurons in a circuit must be tightly regulated to ensure proper circuit function. While much is known about the processes that promote synaptogenesis, far less has been discovered about the mechanisms that negatively regulate synaptogenesis. We seek to identify and elucidate these molecular pathways, informing our understanding of mechanisms that may underlie devastating neurological disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1)
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Leenders, Miriam
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San Jose State University
Schools of Arts and Sciences
San Jose
United States
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