Attempts to Restore Visual Function after Optic Nerve Damage in Adult Mammals

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Tomomitsu Miyoshi, Takuji Kurimoto and Yutaka Fukuda Abstract

Retinal ganglion cells (RGCs) and their axons, i.e., optic nerve (ON) fibers, provide a good experimental model for research on damaged CNS neurons and their functional recovery. After the ON transection most RGCs undergo retrograde and anterograde degeneration but they can be rescued and regenerated by transplantation of a piece of peripheral nerve (PN). When the nerve graft was bridged to the visual center, regenerating RGC axons can restore the central visual projection. Behavioral recovery of relatively simple visual function has been proved in such PN-grafted rodents. Intravitreal injections of various neurotrophic factors and cytokines to activate intracellular signaling mechanism of RGCs and electrical stimulation to the cut end of ON have promoting effects on their survival and axonal regeneration. Axotomized RGCs in adult cats are also shown to survive and regenerate their axons through the PN graft. Among the cat RGC types, Y cells, which function as visual motion detector, tend to survive and regenerate axons better than others. X cells, which are essential for acute vision, suffer from rapid death after ON transection but they can be rescued by intravitreal application of neurotrophins accompanied with elevation of cAMP. To restore visual function in adult mammals with damaged optic pathway, the comprehensive and integrative strategies of multiple approaches will be needed, taking care of functional diversity of RGC types.

Optic Nerve Regeneration and Functional Recovery of Vision in Rodents

During embryonic development the neural retina and optic nerve (ON) are formed as bilateral protrusions from a frontal part of the neural tube and thus these tissues are a part of the CNS. Basic studies on deterioration of the retina and the ON after the damage in the central visual pathway and various attempts to promote recovery of visual function will certainly benefit our knowledge on brain damage and its repair in general. The retinal ganglion cells (RGCs) send visual information, processed within the retina, to various visual centers of the brain through their axons in the ON. When the ON is severely injured, almost all RGCs die in adult mammals and there is no spontaneous axonal regeneration through the original optic pathway. However, these axotomized RGCs can regenerate axons when a segment of peripheral nerve (PN) is grafted to their cut ends.1'2 Proportion of the RGCs with regenerated axons was, however, only 2-5% and even the best case approximately 10% in adult rats.2 When

Brain Repair, edited by Mathias Bahr. ©2006 Eurekah.com and Kluwer Academic / Plenum Publishers.

the opposite end of the PN graft was bridged to the superior colliculus (SC), regenerating axons make synaptic contacts with proper target neurons.2'3 The visual function of regenerated ON axons and re-established retino-collicular projection has been proved by electrophysiological recordings of single unit activities. Regenerated RGC axons, when recorded in the PN graft, revealed typical visual responses of ON, OFF or ON-OFF center with some surround.4 Transsynaptic activation of re-innervated SC neurons was verified by electrical stimulation of the PN graft and visual stimulation to the operated eye.5"7

The behavioral evidence for the recovery of visual function in PN-grafted rodents has also been presented. Thanos et al8 have first reported that pupillary light response could be recovered in ON-damaged rats 8 and 12 weeks after PN transplantation between the ON stump and the pretectum, though the response was weaker than in intact rats. After PN grafting into the SC in hamsters, Sasaki et al9 have proved that these animals could learn avoidance behavior using light as conditioned stimulus. As shown in Figure 1A, the shutde box was divided into two chambers by a partition which was low enough for the hamster to jump over. When the hamsters did not jump into the other chamber within ten seconds after the light on at the ceiling of shutde box, they received electrical shocks to their foot. A session of thirty or fifty trials of such avoidance task was performed for 10 consecutive days. The hamsters with intact visual system acquired the avoidance behavior as the session proceeded, and achieved about 40% success trials after 10 sessions (Fig. IB). Blind hamsters with bilateral ON transection did not show any improvement in the success rate of avoidance. On the other hand, the hamsters with PN grafts between the ON stump and the SC (the opposite ON was transected) showed a gradual increase in success rate although the extent was lower than that in normal hamsters (Fig. IB). Sasaki etal10,11 have further succeeded to show behavioral recovery of visual function in PN-grafted hamsters by using more natural paradigms such as counting spontaneous ambulating activity in light and dark conditions and measuring bodily movement coincided with EEG desynchronization induced by light. On the other hand, Thanos et al12 have reported in PN-grafted rats that they could discriminate between vertical and horizontal stripes, with some morphological and electrophysiological evidence for restoration of retinotopic representation in reconstructed retino-collicular pathway.

Attempts to Promote RGC Survival and Their Axonal Regeneration in Rodents

As described above, at present only a small proportion of axotomized RGCs regenerate-their axons through the PN graft so that only a limited recovery of visual function can be expected. To restore higher visual function such as acute vision, shape or velocity discrimination, further efforts should be directed to the followings: (1) to increase the number of surviving RGCs, (2) to increase the number of regenerating RGC axons, and (3) to make retinotopic connection to the target neurons in visual centers.

After intraorbital ON transection, rat's RGCs start to die on day 3 and the survival proportion rapidly decreases to 10% of the normal on day 1413 and then after the decrease was gradual.14The prevention of retrograde death of RGCs after ON transection is the first step for better recovery of visual function after PN grafting. Intravitreal injections of various neurotrophic factors have been shown to rescue axotomized RGCs from retrograde cell death in adult rats: NGF,15 BDNF,16,17 NT-4/5,18,19 CNTF,16 FGF,20 IGF,21 GDNF22"24 and Neurturin.24 The effect of peptidic neurotrophic factor such as BDNF and CNTF on RGC survival was dramatically enhanced by intracellular elevation of cAMP.25 Other bioactive molecules such as TNF-a,26 macrophage/microglia inhibitory factor (MIF),27,28 caspase inhibitor29 and Bax antisense oligonucleotide30 were also reported to be effective. In addition, various molecules, cells and tissues derived from in vivo animal revealed promoting effect on RGC survival: PN,31"33 Schwann cells,34 activated macrophages,35 collicular proteoglycan,36 an artificial graft with

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