The regularity of neuronal cell bodies and processes is one of the most striking features of the nervous system and is crucial for cognitive function.
The aim of this proposal is to understand the development and function of dendritic pattering of neurons in the central nervous system. The mammalian retina is an excellent system for the study of neural development due to its regularity, defined cell types, and the ability to present i with relevant stimuli, that is patterned light. The focus of this study is on the patterning of reinal starburst amacrine cell (SAC) dendrites and direction- selective retinal circuits. SACs are crucial for direction-selective retinal computations by retinal ganglion cells, the structure's output to higher brain centers. The stereotyped dendritic morphology of SACs and their precise connectivity to direction-selective ganglion cells are thought to be crucial for the function of direction-selective retinal circuits, but the mechanism of this dendritic patterning and the functional consequences of its disruption have not been tested direction. Without the gamma-protocadherin (Pcdhg) family of adhesion molecules, SACs lose the ability to pattern their dendrites properly. SAC dendrites normally grow out radially from the cell body avoiding each other without avoiding other SACs in the area;however, without Pcdhgs, the dendrites of an individual SAC cross over and fasciculate with each other.
The aims of this proposal are to (1) understand how the expression of Pcdhgs underlies SAC dendritic patterning, (2) determine the developmental progression of SAC dendritic patterning, and (3) understand the role of radially symmetric SAC dendritic arbor for computation of direction-selectivity by retinal ganglion cells.
The first aim will be addressed by expression profiling of Pcdhgs in individual SACs.
The second aim will be accomplished by imaging of SAC dendrite development in retinal explants.
The third aim will be carried out using electrophysiology while presenting visual stimuli to acute retinal preparations. Understanding the different aspects of neural circuit development is crucial for understanding how different disorders of the nervous system take effect. Many disorders of the nervous system are thought to be disorders of connectivity between neurons, so studying how neurons make decisions about connectivity normally will help the scientific community better understand the subtle changes that are observed in pathological situations.

Public Health Relevance

The proper connections made between individual neurons are essential for brain function. Understanding the logic that the brain uses to make these connections will help the scientific community understand what happens in pathological situations, when connections are made incorrectly. Hopefully, these studies will help in the treatment of developmental brain disorders and improve the quality of life for the public.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F05-P (20))
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Talley, Edmund M
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Harvard University
Schools of Medicine
United States
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Ing-Esteves, Samantha; Kostadinov, Dimitar; Marocha, Julie et al. (2018) Combinatorial Effects of Alpha- and Gamma-Protocadherins on Neuronal Survival and Dendritic Self-Avoidance. J Neurosci 38:2713-2729
Kostadinov, Dimitar; Sanes, Joshua R (2015) Protocadherin-dependent dendritic self-avoidance regulates neural connectivity and circuit function. Elife 4:
Lefebvre, Julie L; Kostadinov, Dimitar; Chen, Weisheng V et al. (2012) Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. Nature 488:517-21