Strategies to Promote Long-Distance Optic Nerve Regeneration

Abstract

Mammalian retinal ganglion cells (RGCs) in the central nervous system (CNS) often die after optic nerve injury and surviving RGCs fail to regenerate their axons, eventually resulting in irreversible vision loss. Manipulation of a diverse group of genes can significantly boost optic nerve regeneration of mature RGCs by reactivating developmental-like growth programs or suppressing growth inhibitory pathways. By injury of the vision pathway near their brain targets, a few studies have shown that regenerated RGC axons could form functional synapses with targeted neurons but exhibited poor neural conduction or partial functional recovery. Therefore, the functional restoration of eye-to-brain pathways remains a greatly challenging issue. Here, we review recent advances in long-distance optic nerve regeneration and the subsequent reconnecting to central targets. By summarizing our current strategies for promoting functional recovery, we hope to provide potential insights into future exploration in vision reformation after neural injuries.

Keywords: axon regeneration; functional recovery; glaucoma; optic nerve; retinal ganglion cells.

Figure 1

The promoting capacity of known treatments on optic nerve regeneration in vivo. To regain visual function, regenerating optic nerve axons need to cross the optic chiasm (OX) and reach specific nuclei in the brain, including the suprachiasmatic nucleus (SCN), medial terminal nucleus (MTN), thalamic ventral or dorsal lateral geniculate nucleus (vLGN, dLGN), intergeniculate leaflet (IGL), the nucleus of the optic tract (NOT), olivary pretectal nucleus (OPN), and superior colliculus (SC). Manipulation of a single factor, such as Pten knockout (PTEN KO), IL6 expression, or Sox11 overexpression (SOX11 OE), is unlikely to enhance optic nerve regeneration to reach the OX. However, combinatorial approaches with multiple factors can induce longer distance axon regeneration to reach and cross the OX. In a few cases, it was reported that a combination of multiple factors, such as Pten/Socs3 co-deletion, inflammation/cAMP/Pten knockout, or Rheb1 overexpression/visual stimulation, could enhance optic nerve regeneration to reconnect with selected brain nuclei.

Figure 2

Functionally rewiring the eye-to-brain connections. The first step of an ideal repair strategy should be promoting sufficient long-distance regeneration of injured retinal ganglion cell (RGC) axons back to their original targets. Second, the regenerating axons need to be properly guided through the optic chiasm (OX) and reach their original innervating targets in the brain, which each mediates different visual functions. Third, for functional recovery, the regenerating axons need to reform functional synapses with the appropriate targets and remyelinate for electrical conduction. Finally, the optic nerve circuitries, governing the whole-animal physiological state, visually-driven reflexive behaviors, and complex visual features, could be re-established to restore visual functions.