How terminal Schwann cells (tSCs), glia that cover the terminal branches of motoneurons at the neuromuscular junction (NMJ), function in synaptic maintenance and turnover remains incompletely understood. A variety of observations suggest that defects in axonal-glial interactions at the synapse and along the projecting axons lead to degenerative disease. The present project proposes a study of the role of tSCs in the normal, ongoing turnover of synaptic contacts at NMJs. While most of the area in which the motoneuron terminal contacts muscle fibers is stable in young adult mice, the site where the nerve enters the NMJ is less so. Here, contact sites are commonly lost;and this loss is associated with glial changes, including the myelination of terminal branches that were previously synaptic. This kind of loss appears to be a progressive phenomenon, becoming more prevalent with time and quite prevalent in aged animals. We have generated transgenic mice whose expression of fluorescent proteins allows the repeated, vital imaging of the cellular components of the synapse and have shown loss of synaptic sites and some of their associated glial changes. We have shown that individual tSCs partition their coverage of the synaptic site among themselves. However, we have been unable to visualize individual glial cells in a vital fashion. We have now generated mice that express a photoswitchable fluorescent protein in their SCs. This allows the visualization, marking and examination of individual cells. We will (1) utilize these mice to determine how individual tSCs participate in synaptic changes. (2) We will use electron microscopy to examine the portions of individual synapses in the process of change to determine what the light microscopic features mean at the ultrastructural level and to examine the possibility that the glia are stripping synapses from the muscle fiber. We will also determine when individual tSCs in the junction begin to express certain markers of altered glial differentiation and how these alterations relate to ongoing synaptic change. (3) Finally we will examine neuregulin signaling believed to lead to differentiation of SCs to a myelinating phenotype. We will examine the distribution of this signaling molecule in motor nerve terminals and determine how overexpression of this signaling molecule alters the number and behavior of synaptic glia and leads to structural changes in the synapse. The results of the proposed work should expand our understanding of the interactions of glia and neurons at synapses.

Public Health Relevance

Existing and new genetically modified mice will be used to explore, via vital imaging, the function of glia at a simple, model synapse, the neuromuscular junction. The proposed research will investigate the hypothesis that glial cells initiate synaptic remodeling that occurs normally in young adults but becomes pronounced in aging. The proposed work also has relevance to dysmyelinating diseases that ultimately lead to degeneration of peripheral motor neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020480-26
Application #
8274684
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Porter, John D
Project Start
1984-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
26
Fiscal Year
2012
Total Cost
$322,283
Indirect Cost
$107,908
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Li, Yue; Lee, Young il; Thompson, Wesley J (2011) Changes in aging mouse neuromuscular junctions are explained by degeneration and regeneration of muscle fiber segments at the synapse. J Neurosci 31:14910-9
Li, Yue; Thompson, Wesley J (2011) Nerve terminal growth remodels neuromuscular synapses in mice following regeneration of the postsynaptic muscle fiber. J Neurosci 31:13191-203
Lee, Young Il; Mikesh, Michelle; Smith, Ian et al. (2011) Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons. Dev Biol 356:432-44
Kang, Hyuno; Tian, Le; Son, Young-Jin et al. (2007) Regulation of the intermediate filament protein nestin at rodent neuromuscular junctions by innervation and activity. J Neurosci 27:5948-57
Hayworth, Christopher R; Moody, Susan E; Chodosh, Lewis A et al. (2006) Induction of neuregulin signaling in mouse schwann cells in vivo mimics responses to denervation. J Neurosci 26:6873-84
Zuo, Yi; Lubischer, Jane L; Kang, Hyuno et al. (2004) Fluorescent proteins expressed in mouse transgenic lines mark subsets of glia, neurons, macrophages, and dendritic cells for vital examination. J Neurosci 24:10999-1009
Kang, Hyuno; Tian, Le; Thompson, Wesley (2003) Terminal Schwann cells guide the reinnervation of muscle after nerve injury. J Neurocytol 32:975-85
Love, Flora M; Son, Young-Jin; Thompson, Wesley J (2003) Activity alters muscle reinnervation and terminal sprouting by reducing the number of Schwann cell pathways that grow to link synaptic sites. J Neurobiol 54:566-76
Trachtenberg, J T (1998) Fiber apoptosis in developing rat muscles is regulated by activity, neuregulin. Dev Biol 196:193-203
Kopp, D M; Trachtenberg, J T; Thompson, W J (1997) Glial growth factor rescues Schwann cells of mechanoreceptors from denervation-induced apoptosis. J Neurosci 17:6697-706

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