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The Journal of Neuroscience, May 15, 2002, 22(10):3977-3986

TrkB Gene Transfer Protects Retinal Ganglion Cells from Axotomy-Induced Death In Vivo

Li Cheng¹, Przemyslaw Sapieha¹, Pavla Kittlerová², William W. Hauswirth³, and Adriana Di Polo¹

¹ Department of Pathology and Cell Biology, Université de Montréal, Montreal, Quebec H3T 1J4, Canada, ² Montreal General Hospital Research Institute, McGill University, Montreal, Quebec H3G 1A4, Canada, and ³ Department of Ophthalmology and Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610-0284

Injury-induced downregulation of neurotrophin receptors may limit the response of neurons to trophic factors, compromising their ability to survive. We tested this hypothesis in a model of CNS injury: retinal ganglion cell (RGC) death after transection of the adult rat optic nerve. TrkB mRNA rapidly decreased in axotomized RGCs to ~50% of the level in intact retinas. TrkB gene transfer into RGCs combined with exogenous BDNF administration markedly increased neuronal survival: 76% of RGCs remained alive at 2 weeks after axotomy, a time when >90% of these neurons are lost without treatment. Activation of mitogen-activated protein kinase, but not phosphatidylinositol-3 kinase, was required for TrkB-induced survival. These data provide proof-of-principle that enhancing the capacity of injured neurons to respond to trophic factors can be an effective neuroprotective strategy in the adult CNS.

Key words: retinal ganglion cells; axotomy; gene transfer; TrkB; MAP kinase; cell survival

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22103977-10$05.00/0

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