The proposed research is designed to elucidate the cellular and molecular mechanisms underlying the recently identified roles of the different isoforms of NCAM in bringing about the structural and functional maturation of the neuromuscular junction required for normal motor function. It is specifically designed to define the role of the 140 and/or 120 kD isoform of NCAM in the down regulation of the immature, brefeldin A and L-type Ca+2 channel sensitive, immature vesicle cycling/release mechanism from the axon. It will also explore how the 180 kD isoform results in the appropriate localization of presynaptic molecules required for mature, effective transmission. Finally, it will elucidate the role of the highly conserved C-terminal domain of NCAM, which in concert with myosin light chain kinase and PCKe, has been shown by this work to be required to sustain effective transmission at adult synapses in response to repetitive stimulation. These goals will be achieved by electrical recordings and FM1-43 imaging of synapse formation in motoneuron myotube cultures from wild type mice or those lacking specific NCAM isoforms. Intracellular signaling and protein-protein interactions in isolated adult nerve-muscle preparations will be investigated by the introduction of specific blocking peptides into the presynaptic terminal. The formation of effective synapses is essential for normal neural function in both the peripheral and central nervous system. Mutant mice lacking NCAM, while viable and fertile, display motor defects as well as alterations in learning and memory. Similar defects are likely to occur in humans with mutations in the NCAM gene. In addition, these studies will provide insight into steps in presynaptic maturation and vesicle cycling mechanisms that are required for junctions to function at high but physiological repetition rates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS023678-18A2
Application #
6781306
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
1985-09-01
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
18
Fiscal Year
2004
Total Cost
$283,050
Indirect Cost
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Hata, Katsusuke; Maeno-Hikichi, Yuka; Yumoto, Norihiro et al. (2018) Distinct Roles of Different Presynaptic and Postsynaptic NCAM Isoforms in Early Motoneuron-Myotube Interactions Required for Functional Synapse Formation. J Neurosci 38:498-510
Maeno-Hikichi, Yuka; Polo-Parada, Luis; Kastanenka, Ksenia V et al. (2011) Frequency-dependent modes of synaptic vesicle endocytosis and exocytosis at adult mouse neuromuscular junctions. J Neurosci 31:1093-105
Kariya, Shingo; Park, Gyu-Hwan; Maeno-Hikichi, Yuka et al. (2008) Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum Mol Genet 17:2552-69
Hanson, M Gartz; Milner, Louise D; Landmesser, Lynn T (2008) Spontaneous rhythmic activity in early chick spinal cord influences distinct motor axon pathfinding decisions. Brain Res Rev 57:77-85
Hata, Katsusuke; Polo-Parada, Luis; Landmesser, Lynn T (2007) Selective targeting of different neural cell adhesion molecule isoforms during motoneuron myotube synapse formation in culture and the switch from an immature to mature form of synaptic vesicle cycling. J Neurosci 27:14481-93
Herlitze, Stefan; Landmesser, Lynn T (2007) New optical tools for controlling neuronal activity. Curr Opin Neurobiol 17:87-94
Hanson, M Gartz; Landmesser, Lynn T (2006) Increasing the frequency of spontaneous rhythmic activity disrupts pool-specific axon fasciculation and pathfinding of embryonic spinal motoneurons. J Neurosci 26:12769-80
Jevsek, Marko; Jaworski, Alexander; Polo-Parada, Luis et al. (2006) CD24 is expressed by myofiber synaptic nuclei and regulates synaptic transmission. Proc Natl Acad Sci U S A 103:6374-9
Li, Xiang; Gutierrez, Davina V; Hanson, M Gartz et al. (2005) Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin. Proc Natl Acad Sci U S A 102:17816-21
Polo-Parada, Luis; Plattner, Florian; Bose, Christian et al. (2005) NCAM 180 acting via a conserved C-terminal domain and MLCK is essential for effective transmission with repetitive stimulation. Neuron 46:917-31

Showing the most recent 10 out of 54 publications