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Editors Selection IGR 13-1

Basic Research: BDNF and ganglion-cell survival

Comment by Robert Nickells on:

25180 Combined application of BDNF to the eye and brain enhances ganglion cell survival and function in the cat after optic nerve injury, Weber AJ; Viswanáthan S; Ramanathan C et al., Investigative Ophthalmology and Visual Science, 2010; 51: 327-334

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The neurotrophin hypothesis of ganglion-cell death in glaucoma is based on the principal that a retrograde supply of neurotrophins is critical for ganglion-cell soma survival. Because axonal transport is compromised in glaucoma, it follows that the loss of neurotrophins flowing into the eye is a primary trigger leading to ganglion-cell death. Supporting this, a variety of studies showed that ganglion-cell survival, after a lesion to the optic nerve, could be enhanced by intravitreal delivery of a diverse array of neurotrophins. Universally, however, the effect of exogenous neurotrophin therapy to the eye was both modest, and transient.

In this new study, Weber et al. (131) take a new approach to neurotrophin therapy. They study the delivery of brain-derived neurotrophic factor (BDNF) on ganglion-cell survival in a cat model of mild/moderate optic nerve crush. BDNF, which is one of the most potent neurotrophins for ganglion-cell survival, when applied directly to the eye as an intravitreal injection, had the expected modest and transient effect on cat ganglion-cell survival one week after crush. If BDNF was applied both as an injection into the vitreous, and infused directly into the visual cortex, however, the effects were dramatic. Nearly normal numbers of ganglion cells remained in the damaged eyes, even two weeks after crush surgery. The authors also evaluated inner retinal function using pattern electroretinograms (PERG). At one week, PERG responses were normal for eyes treated with BDNF, either singly or combined. By two weeks, only eyes treated using the combined therapy showed nearly normal PERG responses.

The authors speculate on the mechanism of neuroprotection provided by the combined therapy. They note that the few animals they treated with BDNF applied to the cortex had an even less protective effect compared to intravitreal injection alone. This suggested that the intravitreal injection was essential to protect the ganglion-cell somas from the immediate trauma of axonal damage. The effect from cortical infusion may be required for more long term survival. Important players in this story are the target neurons in the lateral geniculate nucleus (LGN). Others have elegantly demonstrated that these cells are also adversely affected when the optic nerve is damaged. The basic visual pathway in the cat follows ganglion-cell axons projecting to these target neurons, which then project to neurons in the visual cortex. Furthermore, neurons in layer 6 of the cortex project back to the LGN. It is possible that the application of BDNF directly to the cortex has two important roles in protecting LGN neurons. First, LGN neurons can take up the BDNF directly and transport this neurotrophin back to their somas in a retrograde fashion. Second, cortical neurons in layer 6 may become stimulated and provide trophic support to the LGN by their increased electrical activity, thus providing an anterograde effect. The ganglion cells ultimately benefit because of the increased brain stimulation, and by the fact that they probably still have partially intact and functioning axons. A condition that we assume is much like their condition in glaucoma.

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