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Brain Advance Access originally published online on January 17, 2006
Brain 2006 129(4):1014-1026; doi:10.1093/brain/awl015
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Synergistic action of brain-derived neurotrophic factor and lens injury promotes retinal ganglion cell survival, but leads to optic nerve dystrophy in vivo

Vincent Pernet1 and Adriana Di Polo1,2

1 Department of Pathology and Cell Biology and 2 Department of Ophthalmology, Université de Montréal, Quebec, Canada

Correspondence to: Adriana Di Polo, Department of Pathology and Cell Biology Université de Montréal 2900, Boul. Edouard-Montpetit Pavillon Roger Gaudry, Room N-535 Montreal, Quebec H3T 1J4, Canada E-mail: adriana.di.polo{at}umontreal.ca

Trauma or disease in the CNS often leads to neuronal death and consequent loss of functional connections. The idea has been put forward that strategies aimed at repairing the injured CNS involve stimulation of both neuronal survival and axon regeneration. We tested this hypothesis in the adult rat retinocollicular system by combining two strategies: (i) exogenous administration of brain-derived neurotrophic factor (BDNF), a potent survival factor for damaged retinal ganglion cells (RGCs) and (ii) lens injury, which promotes robust growth of transected RGC axons. Our results demonstrate that BDNF and lens injury interact synergistically to promote neuronal survival: 71% of RGCs were alive at 2 weeks after optic nerve injury, a time when only ~10% of these neurons remain without treatment. Intravitreal injection of BDNF, however, led to regeneration failure following lens injury. The effect of BDNF could not be generalized to other growth factors, as ciliary neurotrophic factor did not cause a significant reduction of lens injury-induced regeneration. Growth arrest in optic nerves treated with BDNF and lens injury correlated with the formation of hypertrophic axonal swellings in the proximal optic nerve. These swellings were filled with numerous vesicular bodies, disorganized neurofilaments and degenerating organelles. Our results demonstrate that: (i) increased neuronal survival does not necessarily lead to enhanced axon regeneration and (ii) activation of survival and growth pathways may produce axonal dystrophy similar to that found in neurodegenerative disorders including glaucoma, Alzheimer's disease and multiple sclerosis. We propose that loss of axonal integrity may limit neuronal recovery in the injured, adult CNS.

Key Words: brain-derived neurotrophic factor; lens injury; retinal ganglion cells; neuroprotection; axonal regeneration

Abbreviations: AAV = adeno-associated virus; BDNF = brain-derived neurotrophic factor; CNTF = ciliary neurotrophic factor; GFAP = glial fibrillary acidic protein; GFP = green fluorescent protein; RGCs = retinal ganglion cells

Received July 12, 2005. Revised December 14, 2005. Accepted December 22, 2005.


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