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The Journal of Neuroscience, February 1, 2002, 22(3):931-945

Mechanisms of the Release of Anterogradely Transported Neurotrophin-3 from Axon Terminals

XiaoXia Wang¹, Rafal Butowt¹, Michael R. Vasko², and Christopher S. von Bartheld¹

¹ Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89557, and ² Department of Pharmacology and Toxicology, University of Indiana School of Medicine, Indianapolis, Indiana 46202-5120

Neurotrophins have profound effects on synaptic function and structure. They can be derived from presynaptic, as well as postsynaptic, sites. To date, it has not been possible to measure the release of neurotrophins from axon terminals in intact tissue. We implemented a novel, extremely sensitive assay for the release and transfer of anterogradely transported neurotrophin-3 (NT-3) from a presynaptic to a postsynaptic location that uses synaptosomal fractionation after introduction of radiolabeled NT-3 into the retinotectal projection of chick embryos. Release of the anterogradely transported NT-3 in intact tissue was assessed by measuring the amount remaining in synaptosomal preparations after treatment of whole tecta with pharmacological agents. Use of this assay reveals that release of NT-3 from axon terminals is increased by depolarization, calcium influx via N-type calcium channels, and cAMP analogs, and release is most profoundly increased by excitation with kainic acid or mobilization of calcium from intracellular stores. NT-3 release depends on extracellular sodium, CaM kinase II activity, and requires intact microtubules and microfilaments. Dantrolene inhibits the high potassium-induced release of NT-3, indicating that release of calcium from intracellular stores is required. Tetanus toxin also inhibits NT-3 release, suggesting that intact synaptobrevin or synaptobrevin-like molecules are required for exocytosis. Ultrastructural autoradiography and immunolabel indicate that NT-3 is packaged in presumptive large dense-core vesicles. These data show that release of NT-3 from axon terminals depends on multiple regulatory proteins and ions, including the mobilization of local calcium. The data provide insight in the mechanisms of anterograde neurotrophins as synaptic modulators.

Key words: neurotrophic factors; secretion; presynaptic terminals; calcium; axonal transport; neurotrophin; synapse; synaptic transmission

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Copyright © 2002 Society for Neuroscience  0270-6474/02/223931-15$05.00/0

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