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(Investigative Ophthalmology and Visual Science. 2003;44:791-798.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.02-0557
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Mechanism by which Brain-Derived Neurotrophic Factor Increases Dopamine Release from the Rabbit Retina

Michael Neal,1 Joanna Cunningham,1 Isobel Lever,2 Sophie Pezet,2 and Marzia Malcangio2

1From the Department of Vision and Ophthalmology and the 2Neuroscience Research Center, King’s College London, St. Thomas’ Hospital, London, United Kingdom.

PURPOSE. To determine whether BDNF modulates the release of dopamine from amacrine cells in the rabbit retina.

METHODS. Isolated retinas from rabbits killed with pentobarbital were incubated in Krebs bicarbonate medium containing pargyline, nomifensine, and bovine serum albumin. The medium was changed at 10-minute intervals, and the dopamine in the resultant samples measured by HPLC. Five samples were collected to establish the spontaneous resting release of dopamine, and then the retina was exposed to BDNF for a further two collection periods. Double-label immunohistochemistry was used to identify tyrosine hydroxylase containing neurons and to localize TrkB (BDNF) receptors.

RESULTS. Exposure of the retina to BDNF (70–150 ng/mL) caused a concentration-dependent increase in the release of dopamine. The maximum effect was produced by 150 ng/mL BDNF, which almost doubled the release. The BDNF-evoked release was abolished in low-calcium/high-magnesium medium. It was also prevented by the tyrosine kinase inhibitors k252a and genistein, the phospholipase inhibitor U73122, and the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitors thapsigargin and cyclopiazonic acid. Antagonists of {gamma}-aminobutyric acid (GABA) and glutamate did not affect the BDNF-evoked release of dopamine. ELISA assay confirmed the presence of BDNF in the retina, and immunohistochemistry revealed that some tyrosine hydroxylase–containing neurons possessed TrkB receptors.

CONCLUSIONS. BDNF quickly (within minutes) increases the release of dopamine from amacrine cells in the rabbit retina by an action that is likely to involve TrkB receptors. The mechanism linking TrkB receptor activation to the release of dopamine involves activation of phospholipase-C{gamma}, with the subsequent production of IP3 and calcium release from the endoplasmic reticulum. The resultant capacitative entry of calcium seems to be the actual trigger for BDNF-induced release of dopamine.




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R. A. Bush, B. Lei, W. Tao, D. Raz, C.-C. Chan, T. A. Cox, M. Santos-Muffley, and P. A. Sieving
Encapsulated Cell-Based Intraocular Delivery of Ciliary Neurotrophic Factor in Normal Rabbit: Dose-Dependent Effects on ERG and Retinal Histology
Invest. Ophthalmol. Vis. Sci., July 1, 2004; 45(7): 2420 - 2430.
[Abstract] [Full Text] [PDF]


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