Neurotrophic factors are messengers for communication between neurons. They regulate neuronal differentiation and may be instrumental in the formation, stabilization and plasticity of synapses. Targeting of neurotrophic factors to their proper intracellular destination is essential for trophic signaling. The application's central aim is to elucidate pathways of internalized neurotrophins and to reveal mechanisms of their axonal transport and release from synapses in the visual system. The proposed studies will utilize an in-vivo system in which the transport of trophic factors can be quantified. The developing visual system (retinotectal and isthmo-optic projections) of chick embryos is a unique model which allows the controlled introduction of iodinated trophic factors into the posterior chamber of the eye and the study of retrograde and anterograde transport to distant targets. Experimental techniques have been designed to determine the mechanisms of release at the axon terminus and the function and significance of axodendritic transfer of neurotrophins. Specifically, the proposed studies will identify the source of neurotrophin-3 in the retina and use crosslinkers and antibodies to determine which receptors bind neurotrophins during anterograde and retrograde transport. The organelles in which internalized neurotrophins are sorted and in which anterograde transport and release takes place will be characterized at the ultrastructural level. The hypothesis that neurotrophins are co-localized with neurotransmitters or with neuropeptides in synaptic vesicles will be tested. The mechanisms of release at the axon terminus will be explored by measuring neurotrophin content in synaptosomes after treatment with pharmacological substances. It will be further examined if anterogradely transported neurotrophins promote synaptogenesis. The combination of molecular, pharmacological and ultrastructural approaches in an advantageous model system will allow the investigator to answer questions about trafficking of neurotrophins which are crucial to an understanding of how these factors may regulate neuronal survival as well as synaptic plasticity in the developing visual system and other parts to the brain. Neurotrophins are important regulators during the development of the visual system as well as potential therapeutic agents in degenerative retinal disease and after optic nerve injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS035931-01A1
Application #
2503731
Study Section
Neurology C Study Section (NEUC)
Program Officer
Leblanc, Gabrielle G
Project Start
1998-01-01
Project End
2000-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Von Bartheld, Christopher S; Altick, Amy L (2011) Multivesicular bodies in neurons: distribution, protein content, and trafficking functions. Prog Neurobiol 93:313-40
Altick, Amy L; Baryshnikova, Larisa M; Vu, Tania Q et al. (2009) Quantitative analysis of multivesicular bodies (MVBs) in the hypoglossal nerve: evidence that neurotrophic factors do not use MVBs for retrograde axonal transport. J Comp Neurol 514:641-57
Butowt, Rafal; von Bartheld, Christopher S (2009) Fates of neurotrophins after retrograde axonal transport: phosphorylation of p75NTR is a sorting signal for delayed degradation. J Neurosci 29:10715-29
Rind, Howard B; Butowt, Rafal; von Bartheld, Christopher S (2005) Synaptic targeting of retrogradely transported trophic factors in motoneurons: comparison of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and cardiotrophin-1 with tetanus toxin. J Neurosci 25:539-49
von Bartheld, Christopher S (2004) Axonal transport and neuronal transcytosis of trophic factors, tracers, and pathogens. J Neurobiol 58:295-314
Wang, Xiaoxia; Butowt, Rafal; von Bartheld, Christopher S (2003) Presynaptic neurotrophin-3 increases the number of tectal synapses, vesicle density, and number of docked vesicles in chick embryos. J Comp Neurol 458:62-77
von Bartheld, C (2002) Counting particles in tissue sections: choices of methods and importance of calibration to minimize biases. Histol Histopathol 17:639-48
Wang, XiaoXia; Butowt, Rafal; Vasko, Michael R et al. (2002) Mechanisms of the release of anterogradely transported neurotrophin-3 from axon terminals. J Neurosci 22:931-45
Rind, Howard B; von Bartheld, Christopher S (2002) Anterograde axonal transport of internalized GDNF in sensory and motor neurons. Neuroreport 13:659-64
Butowt, R; von Bartheld, C S (2001) Sorting of internalized neurotrophins into an endocytic transcytosis pathway via the Golgi system: Ultrastructural analysis in retinal ganglion cells. J Neurosci 21:8915-30

Showing the most recent 10 out of 19 publications