Axon Guidance Molecules and Neural Circuit Remodeling After Spinal Cord Injury

Abstract

…once the development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. Santiago Ramón y CajalCajal's neurotropic theory postulates that the complexity of the nervous system arises from the collaboration of neurotropic signals from neuronal and non-neuronal cells and that once development has ended, a paucity of neurotropic signals means that the pathways of the central nervous system are Bfixed, ended, immutable^. While the capacity for regeneration and plasticity of the central nervous system may not be quite as paltry as Cajal proposed, regeneration is severely limited in scope as there is no spontaneous regeneration of long-distance projections in mammals and therefore limited opportunity for functional recovery following spinal cord injury. It is not a far stretch from Cajal to hypothesize that reappropriation of the neurotropic programs of development may be an appropriate strategy for reconstitution of injured circuits. It has become clear, however, that a significant number of the molecular cues governing circuit development become re-active after injury and many assume roles that paradoxically obstruct the functional re-wiring of severed neural connections. Therefore, the problem to address is how individual neural circuits respond to specific molecular cues following injury, and what strategies will be necessary for instigating functional repair or remodeling of the injured spinal cord.

Cell biology of spinal cord injury and repair

“…Blockade of laminin-integrin interactions can prevent axon growth in vitro (90) and axon regeneration stimulated in vivo after SCI (19). Diffusible chemorepulsion is mediated by Wnt signaling, semaphorins, netrins, and other molecules that create gradients during development (93,96). Interestingly, semaphorins and netrins can be either repellent or attractive to different axons or even to the same axons depending on combinatorial signaling in growth cones (81,82,93).…”

“…Interestingly, semaphorins and netrins can be either repellent or attractive to different axons or even to the same axons depending on combinatorial signaling in growth cones (81,82,93). Roles of these molecules after SCI are being studied (93,96,97). Removal of semaphorins alone or in combination with removal of putative myelin inhibitors is insufficient for spontaneous regrowth of serotonin axons after SCI (98).…”

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…The developing axons of many neurons receive positional information in the form of extracellular Wnt gradients [152,153]. The growing axon is tipped with a highly motile lamellopodial and filopodial structure called the growth cone responsible for detecting and responding to extracellular guidance cues that direct axon outgrowth.…”

Axonal regeneration in zebrafish spinal cord

“…Interestingly, many guidance and synaptogenic cues that regulate neural wiring during CNS development also contribute to the remodeling of axonal connections in injured spinal cord. Apart from several extracellular matrices, many guidance molecules like the netrins, semaphorins, the robo/slit family, ephrins, Wnts, and repulsive guidance molecules have been identified and are known to play a role after SCI in mammals (Giger et al., ; Harel & Strittmatter, ; Hollis, ; Jacobi, Schmalz, & Bareyre, ). It has been suggested that inhibitory and chemo‐repulsive axon guidance molecules are likely to play an important role in synaptic stabilization and limitation of neuronal plasticity in adult life.…”