REVIEW Goal” to discover means to repair RGC con- nections with the brain (https://nei.nih.gov/ audacious). The major questions that drive research on Regenerating optic pathways visual restoration and RGC repair are simple but challenging: What strategies support RGC from the eye to the brain axon regeneration after damage? Can regenerating RGC axons form functional synapses with their Bireswar Laha,1 Ben K. Stafford,1 Andrew D. Huberman1,2,3* targets in the brain? Humans are highly visual. Retinal ganglion cells (RGCs), the neurons that connect Extrinsic factors unique to the CNS the eyes to the brain, fail to regenerate after damage, eventually leading to blindness. limit optic nerve regeneration Here, we review research on regeneration and repair of the optic system. Intrinsic Various environmental influences limit RGC developmental growth programs can be reactivated in RGCs, neural activity can regeneration. Although neurons with cell bodies enhance RGC regeneration, and functional reformation of eye-to-brain connections is in the peripheral nervous system (PNS) avidly possible, even in the adult brain. Transplantation and gene therapy may serve to replace regenerate, neurons such as RGCs, whose cell or resurrect dead or injured retinal neurons. Retinal prosthetics that can restore vision bodies reside in the central nervous system in animal models may too have practical power in the clinical setting. Functional (CNS), fail to reextend after injury (3, 4). Even restoration of sight in certain forms of blindness is likely to occur in human patients if the rodent optic nerve is completely tran- in the near future. sected, a peripheral nerve graft allows RGC axons to regenerate and form synapses with their ight is crucial for humans to navigate the ing their correct synaptic relationships. Un- targets in the brain (5, 6). Thus, the damage en- world. Under normal, healthy conditions, fortunately, mammalian RGC axons do not vironment constrains the regeneration of mature our eyes and brain create sight so automat- regenerate after damage and damaged RGCs rodent RGCs. Unfortunately for humans, the PNS ically that only when our visual pathways eventually die, never to be replaced. So prevalent nerve graft approach holds limited therapeutic S are damaged do we fully appreciate the ex- is this cause for blindness that the U.S. National potential because it involves massive neuro- on June 9, 2017 tent to which eyesight defines our experience. For Eye Institute has set forth as their “Audacious surgeries. Nevertheless, these studies underscore the many who suffer visual impairments, it is ur- gent that we discover strategies to regenerate ret- inal neurons and convert those strategies into clinically viable therapeutics. Vision begins in the retina, the thin trilayered Photoreceptors Light pathway neural tissue at the back of the eye (Fig. 1); there, Horizontal cells Signal output pathway photoreceptors transform light information into Bipolar cells electrical signals that the rest of the visual system can understand. The retinal interneurons—the Amacrine cells horizontal, bipolar, and amacrine cells—then pass Retinal ganglion cells (RGCs) that information to the retinal ganglion cells http://science.sciencemag.org/ (RGCs), the output neurons of the eye. There are ~30 different types of RGCs, each firing action Light response potentials depending on the quality and location Action potentials of visual stimuli in the environment (1). Those Retina action potentials propagate down the optic nerves and into the brain, where they are translated into perceptions and light-mediated behaviors. Downloaded from The importance of retinal ganglion cells RGCs are a bottleneck for vision. Even when the rest of the visual system is healthy, if RGCs are dead or dysfunctional, vision is impossible. RGCs are protected by the sclera, the thick, durable tissue that encompasses the back of the eye. How- ever, the path that RGC axons take to reach the Myelinated brain renders them vulnerable to damage in re- optic nerve sponse to impacts to the head or eye. Glaucoma, with its attendant elevated eye pressure, is the most common cause of irreversible blindness (2). Intact optic nerve Optic nerve damage Research on visual repair has therefore focused Myelin SCIENCE on sustaining RGCs after injury, encouraging axon regrowth down the optic nerve, and reestablish- 1Department of Neurobiology, Stanford University School of Fig. 1. Visual information is transmitted from the eye to the visual centers in the brain via the 2 Medicine, Stanford, CA 94305, USA. Department of optic nerve. (Top)Lightreachingtheretinaisconvertedintoelectrical potentials that eventually cause Ophthalmology, Stanford University School of Medicine, action potentials in the ganglion cells (RGCs). (Middle)Themyelinatedopticnervetransmitsaction Stanford, CA 94305, USA. 3BioX, Stanford University School of Medicine, Stanford, CA 94305, USA. potentials (Bottom left)tothevisualprocessingcentersinthebrain.(Bottom right)Afterdamage, GRAPHIC: ADAPTED BY K.*Corresponding SUTLIFF/ author. Email: [email protected] RGC axons degenerate. In the absence of therapeutic interventions, blindness ensues. Laha et al., Science 356,1031–1034 (2017) 9 June 2017 1of4 REPAIR AND REGENERATION the principle that RGCs can regen- Retina erate if given the appropriate milieu. RGCs Injured RGCs Inhibitory effects of made active myelin proteins Normally, myelin insulates axons, increasing conduction velocity of electrical signals (Fig. 1). In the PNS, where regeneration is inher- Injured RGCs ent to the system, Schwann cells provide myelination. In the CNS, Oligodendrocytes are the myelinat- ing glial cells and have an inhib- itory effect on axon regeneration. Oligodendrocytes present a variety of proteins inhibitory to axon re- Site of optic growth, including myelin-associated nerve damage glycoprotein, the neurite-outgrowth inhibitor “Nogo,” oligodendrocyte- myelin glycoprotein, and semaphor- Fig. 2. Electrical activity can promote RGC axon regeneration. Increasing the activity of RGCs after optic ins (7, 8). Neutralization of these nerve damage can facilitate the repair of degenerating axons in the optic nerve (25, 33), with many extending past proteins has been shown to enhance the site of damage into the brain and partially restoring sight in animal models (25). RGC axon regeneration in vitro (7). However, experiments assessing the consequences mia inhibitory factor, and ciliary neurotrophic considering their clinical applications. First, the of removing these proteins in vivo reveal little factor (CNTF) from glia and other non-neural increase in phosphor-mTOR has to be in place or no regeneration (9), challenging whether cells (16, 17). In the adult, CNTF up-regulates a before axon injury in order for regeneration to on June 9, 2017 these proteins actually constitute major brakes transcriptional pathway involving suppression occur (25). Second, mTOR broadly affects cell on regeneration. Neutralizing Nogo can enhance of cytokine signaling factor 3 (SOCS3) in RGCs, growth (26)andthusmaycauseretinaltumor regeneration if RGCs are shifted into a growth thus limiting axon regeneration (18). In the ab- formation (27). Any therapeutic approach that state (10), but overall, the effects of reducing sence of SOCS3, CNTF can, however, enhance relies on enhancing mTOR signaling thus would myelin-associated proteins on RGC regeneration regeneration by activating gp130-dependent ki- have to include safeguards. Third, mTOR en- are subtle. Thus, attention has expanded to con- nase signaling (19). Thus, the pathways that af- hancement alone (or mTOR plus SOCS3 dele- sider other extrinsic influences that might un- fect RGC regeneration depend on the signaling tion) triggers regeneration of RGC axons only as derlie RGC regenerative failure and that might context, which imposes complexity on potential far as the chiasm (23–25). This suggests that constitute targets for enhancing regeneration in therapeutic strategies. there are inhibitory cues at the optic chiasm and the clinic. Zinc released from amacrine interneurons af- that more potent stimulators of RGC regeneration ter injury is internalized by RGCs and limits their may be needed to inspire RGC axon growth Reactive scarring and inflammation regeneration (20). Other extrinsic factors, how- into the brain. In some mice, axons regenerate http://science.sciencemag.org/ As with any injury, damage to the optic pathway ever, can promote regeneration: Lens injury causes to the optic chiasm but then turn away from the recruits cellular and molecular processes to buf- macrophages to release oncomodulin, which sup- brain and grow into the other optic nerve, toward fer the injury response, some of which affect the ports RGC axon extension via a Ca++/calmodulin the contralateral eye (28). Thus, not all regener- regenerative potential of RGCs (11). Astrocytes— pathway (21). Lesion-reactive cells and proteins ation is productive. Other manipulations such as the glial cells that support synapse development, in both the eye and in the optic nerve can either knockdown of the growth-inhibiting transcrip- transmission, and plasticity (12)—create physi- help or hurt regeneration. The key is to discover tional repressor KLF4 can also encourage RGCs cal and molecular barriers after injury that can when and why. regeneration (29), but again, not the full distance prevent RGC axons from regrowing. Some of back into the brain. Downloaded from these include chondroitin sulfate proteoglycans Intrinsic