Larry Benowitz, PhD

Director
Laboratories for Neuroscience Research in Neurosurgery
Children’s Hospital
Boston, Massachusetts
February 26, 2007

Rewiring the CNS after Injury

Damage to the CNS can result in devastating and often permanent losses of sensory, motor, cognitive, and/or autonomic functions. This poor outcome is due in part to the limited capacity of the CNS to regenerate: few neurons that die are replaced; neurons that remain alive but whose axons are injured cannot regenerate their connections; and undamaged neurons have only a limited ability to form new connections to compensate for ones that have been lost. Our lab has been investigating basic mechanisms that underlie the growth of neural connections, and applying insights from this work to improve functional outcome after CNS injury. In the optic nerve, a CNS pathway in which injured axons normally show no capacity to regrow, activating macrophages in the eye causes the main projection neurons of the eye, the retinal ganglion cells (RGCs), to switch into an active growth state and extend lengthy axons through the optic nerve. This growth requires mannose (a normal constituent of the vitreous); an agent to elevate intracellular cAMP; and oncomodulin, which is a newly discovered polypeptide growth factor that is secreted by macrophages and other cells. Oncomodulin is an atypical Ca2+ -binding protein that binds to a high-affinity receptor on RGCs and stimulates more extensive outgrowth than other known trophic factors. If, at the same time, RGCs are transfected with a gene that renders them unresponsive to inhibitory signals associated with myelin and the glial scar, regeneration is enhanced greatly. Axon outgrowth in this and many other systems is mediated via Mst3b, a neuron-specific homolog of a kinase that controls budding in yeast. Mst3b can be inhibited with the purine analog 6-TG and activated with the purine nucleoside inosine. Blocking Mst3b function or expression suppresses axon growth in culture and in vivo. Conversely, activating this kinase in vivo improves anatomical rewiring and functional outcome after spinal cord injury or stroke. Combined treatments to activate neurons’ growth program while counteracting inhibitory signals enhances rewiring and behavioral outcome to an even greater extent. Such combinational treatments fully restored functional use of the forepaw contralateral to a damaged motor cortex in rats. These and related discoveries may someday enable us to improve functional outcome after CNS injury.

 

 

 

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