Our long-term aim is to understand the mechanism by which neuronal receptive-ending shape is altered by experience. In the nervous system, cell shape is malleable. Neuronal receptive endings, such as dendritic spines and sensory protrusions, are structurally remodelled by experience, and an emerging hypothesis in cellular neuroscience is that these shape changes accommodate and define changes in neuron output. Alterations in receptive-ending structures may, therefore, underlie nervous system plasticity, and may contribute to complex cognitive capacities including learning and memory. How receptive-ending structures acquire and change shape is not well understood;however, it has been assumed that a direct response of postsynaptic neurons to presynaptic activity accounts for most aspects of the phenomenon. Here we challenge this view, suggesting that glial cells associated with receptive endings play major roles in determining receptive-ending shape, and therefore function, together with presynaptic cues. Glia are the most abundant cell type in the human brain, and glia contribute extensively to nervous system disease. However, the roles played by glia in the nervous system remain largely mysterious. Several observations suggest that glia could influence the shapes of neuronal receptive-endings: they are in the right place at the right time, they can sense the postsynaptic milieu, their shapes correlate dynamically with neuronal receptive-ending cell shapes, and mutations in some glial proteins affect receptive ending shape. We previously demonstrated that the nematode C. elegans offers a unique arena in which to explore glial functions in the nervous system, allowing in vivo studies of glial function to be adresed in ways curently not posible in vertebrate settings or even in Drosophila. We propose to use the powerful methods of genetic analysis in C. elegans to uncover 1) the molecular mechanisms by which glia affect neuronal shape, and 2) how remodeling afects neurons function and animal behavior. In the longer term, we plan to explore conservation of the pathways we identify beyond C. elegans. Achieving a comprehensive understanding of the mechanisms that endow nervous systems with anatomic and behavioural plasticity is of paramount importance in understanding the brain. Such an understanding should, eventually, allow us to tackle human disorders, including learning disabilities and autism, which may result from alterations in synaptic function and plasticity.

Public Health Relevance

Achieving a comprehensive understanding of the mechanisms that endow nervous systems with the ability to change in response to experience is of paramount importance in understanding learning, memory and other aspects of the brain. Such an understanding should ultimately allow us to tackle human disorders, including learning disabilities and autism, which may result from defects in such. Our studies describe a novel system, the nematode C. elegans, with the potential to unlock some of the mechanisms leading to experience-dependent changes in behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073121-03
Application #
8258790
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Gubitz, Amelie
Project Start
2010-09-27
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$418,275
Indirect Cost
$170,775
Name
Rockefeller University
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Wallace, Sean W; Singhvi, Aakanksha; Liang, Yupu et al. (2016) PROS-1/Prospero Is a Major Regulator of the Glia-Specific Secretome Controlling Sensory-Neuron Shape and Function in C. elegans. Cell Rep 15:550-62
Singhvi, Aakanksha; Liu, Bingqian; Friedman, Christine J et al. (2016) A Glial K/Cl Transporter Controls Neuronal Receptive Ending Shape by Chloride Inhibition of an rGC. Cell 165:936-48
Shaham, Shai (2015) Glial development and function in the nervous system of Caenorhabditis elegans. Cold Spring Harb Perspect Biol 7:a020578
Kelley, Melissa; Yochem, John; Krieg, Michael et al. (2015) FBN-1, a fibrillin-related protein, is required for resistance of the epidermis to mechanical deformation during C. elegans embryogenesis. Elife 4:
Kutscher, Lena M; Shaham, Shai (2014) Forward and reverse mutagenesis in C. elegans. WormBook :1-26
Pfaff, Samuel; Shaham, Shai (2013) Development of neurons and glia. Curr Opin Neurobiol 23:901-2
Peliti, Margherita; Chuang, John S; Shaham, Shai (2013) Directional locomotion of C. elegans in the absence of external stimuli. PLoS One 8:e78535
Han, Lu; Wang, Ying; Sangaletti, Rachele et al. (2013) Two novel DEG/ENaC channel subunits expressed in glia are needed for nose-touch sensitivity in Caenorhabditis elegans. J Neurosci 33:936-49
Procko, Carl; Lu, Yun; Shaham, Shai (2012) Sensory organ remodeling in Caenorhabditis elegans requires the zinc-finger protein ZTF-16. Genetics 190:1405-15
Oikonomou, Grigorios; Shaham, Shai (2012) On the morphogenesis of glial compartments in the sensory organs of Caenorhabditis elegans. Worm 1:51-5

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