Medical innovations have significantly prolonged the human lifespan during the last century. However, there is still no way to slow brain aging or treat aging-related neuropathologies. Glia outnumber neurons in our nervous system and glia-neuron interactions are essential for synapse formation and stability. It is known that structural alteration and functional decline occur at synapses in both normal aging and neurodegenerative brains (e.g., Alzheimer s and Parkinson s diseases). However, so far there is little known about the dynamism of this synaptic change or the role, if any, glia play. The best way to study synapse/glia changes during aging is to follow the same synapse/glia over time in a living animal. At present, such in vivo studies cannot be easily achieved in the brain, because of the variability of neuron/glia types in the brain and the small size of its synapses. The vertebrate neuromuscular junction (NMJ) is the simplest synapse in the nervous system. Historically, it has contributed greatly to our understanding of synaptic organization and plasticity. The proposed research plan will exploit the mouse NMJ as a model system to examine the structural plasticity of the synapse and associated glia (also called terminal Schwann cells, or TSCs) during aging. The proposed studies combine the in vivo imaging technique with molecular examination and EM reconstruction to elucidate the role of glia in synapse remodeling during aging. The proposal has three specific aims.
Aim 1 examines progressive myelination of Schwann cells in aging and attempts to answer whether such glial changes induce synapse disruption at the axon entry site and affect synapse remodeling in the whole NMJ.
Aim 2 examines the molecular mechanism underlying aging-related synapse loss, and tests whether changes in laminin-TSC interactions lead to invasion of TSCs between muscle fibers and nerve terminals, and whether this leads to removal of synapses during aging. Finally, Aim 3 is designed to determine if reactive TSCs extend processes from remodeling NMJs and guide axon sprouting and reorganization of synaptic connections. Results from the proposed studies will provide important mechanistic insights into the role of glia in aging-related synapse loss, and identify glia as a therapeutic target to ameliorate synaptic pathologies associated with aging.

Public Health Relevance

This project will help to determine the role of glial cells in synaptic changes that occur during aging at the neuromuscular junction. These proposed studies utilize novel methods that allow the investigator to follow structural changes of glia and synapses in living mice, which will provide critical information about how this dynamic process affects normal aging. More importantly, the data may be used to create therapies that target glia for the treatment of neurodegenerative diseases that are characterized by synapse loss, such as Parkinson's Disease and Alzheimer's Disease, or to slow the more debilitating symptoms of normal aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG031871-05
Application #
8234016
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Wise, Bradley C
Project Start
2008-03-15
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$288,169
Indirect Cost
$84,925
Name
University of California Santa Cruz
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Yu, Xinzhu; Zuo, Yi (2011) Spine plasticity in the motor cortex. Curr Opin Neurobiol 21:169-74
Fu, Min; Zuo, Yi (2011) Experience-dependent structural plasticity in the cortex. Trends Neurosci 34:177-87
Xu, Tonghui; Yu, Xinzhu; Perlik, Andrew J et al. (2009) Rapid formation and selective stabilization of synapses for enduring motor memories. Nature 462:915-9
Zuo, Yi; Bishop, Derron (2008) Glial imaging during synapse remodeling at the neuromuscular junction. Neuron Glia Biol 4:319-26