The nervous system comprises tremendous cellular complexity yet its function relies on neurons forming precise patterns of synaptic connections. How individual neurons find and form synapses with the correct partners amidst so many inappropriate ones remains poorly understood. Recent evidence indicates that defects in neural connectivity are an underlying cause of neurological disorders. Thus, identifying molecular mechanisms underlying synaptic connectivity is of major importance to biomedical research and human health. Within the visual systems of vertebrates and invertebrates neurons target axons or dendrites to discrete layers wherein they form synaptic connections, thereby providing a structural basis for the parallel processing of different visual information. In the fly optic lobe synaptic layers contain synapses from many neurons, yet specific neurons within a layer synapse with only a subset of these. How synaptic specificity within layers is achieved is unknown. We have discovered that two families of immunoglobulin (Ig) domain-containing proteins known to engage in heterothallic inter-family interactions are expressed complementarily in a cell-type and layer-specific manner within the fly optic lobe. Different afferent cell types express unique combinations of Dprs (21 genes), and target neurons express Dpr interacting proteins or DIPs (11 members). We hypothesize that different heterothallic Dpr-DIP interactions provide a common mechanism by which afferent neurons establish unique patterns of synaptic connections. To test this hypothesis we will investigate Dpr and DIP function in regulating synaptic specificity within a single afferent cell type, L3 lamina monopolar neurons which synapse with multiple partners within their target layer. We will identify cognate Dpr-DIP pairs expressed by L3 neurons and their synaptic partners and investigate their role in synapse formation. We will also perform gain of function experiments to assess if these Dpr-DIP interactions are sufficient to promote synaptic connectivity. The goal of this research is to identify a molecular strategy underlying synaptic specificity. These studies are designed to address a fundamental gap in our knowledge of the molecular mechanisms underlying neural connectivity and establish a platform for the long term investigation of this issue. We anticipate this research will shed light on strategies for rewiring neural circuits in individuals affected by neurological disease and for creating neural circuits with novel functions. To achieve my short term career goal of establishing an independent research program and earning promotion to Associate Professor in the Department of Neurobiology at Harvard Medical School, and my long term career goal of achieving tenure within the Department, I have assembled a team of mentors consisting of tenured faculty at Harvard Medical School who have helped me establish a career development plan. David Ginty, a Professor in the Department of Neurobiology will serve as my primary mentor, and Michael Greenberg, Professor and Chair of the Department of Neurobiology, and David Van Vactor, Professor in the Department of Cell Biology will be co-mentors. Each member will contribute to my growth as an independent investigator in complementary ways based on their scientific expertise and experience. My career development activities will be focused on: (1) Improvement of mentoring, management and lab organization skills (2) Development of my research program (3) Learning how to best fulfill my institutional responsibilities. Based on my strong career development plan, the expertise of my mentor team and the supportive environment within the Department of Neurobiology and Harvard Medical School I believe I have an excellent opportunity to achieve my career goals.

Public Health Relevance

Our ability to react to our environment (e.g. to avoid being hit by a car) relies on the function of our nervous system, which is made up of cells called neurons that relay sensory information from the periphery (e.g. our eyes) to the brain, and then relay responses from the brain to different muscles that initiate motion. Recent evidence indicates that neurological diseases such as schizophrenia, autism spectrum disorders, epilepsy and intellectual disability result from the inability of neurons to communicate with each other. Our research has the potential to discover how neurons form connections that allow proper communication, and therefore may reveal therapeutic strategies designed to re-establish communication between neurons affected by disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01NS094545-01
Application #
9013957
Study Section
NST-2 Subcommittee (NST)
Program Officer
Mamounas, Laura
Project Start
2015-09-01
Project End
2018-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
Millard, S Sean; Pecot, Matthew Y (2018) Strategies for assembling columns and layers in the Drosophila visual system. Neural Dev 13:11
Peng, Jing; Santiago, Ivan J; Ahn, Curie et al. (2018) Drosophila Fezf coordinates laminar-specific connectivity through cell-intrinsic and cell-extrinsic mechanisms. Elife 7:
Peng, Jing; Santiago, Ivan J; Pecot, Matthew Y (2018) Purification of Low-abundant Cells in the Drosophila Visual System. J Vis Exp :