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The Journal of Neuroscience, September 3, 2008, 28(36):8914-8928; doi:10.1523/JNEUROSCI.1178-08.2008

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Development/Plasticity/Repair
Inactivation of Glycogen Synthase Kinase 3 Promotes Axonal Growth and Recovery in the CNS

John Dill,¹ Hongyu Wang,¹ Fengquan Zhou,² and Shuxin Li¹

¹Department of Neurology and Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, and ²Department of Orthopedic Surgery, Johns Hopkins University, Baltimore, Maryland 20215

Correspondence should be addressed to Shuxin Li, Department of Neurology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-8813. Email: shuxin.li{at}utsouthwestern.edu

Axonal regeneration is minimal after CNS injuries in adult mammals and medical treatments to recover neurological deficits caused by axon disconnection are extremely limited. The failure of axonal elongation is principally attributed to the nonpermissive environment and reduced intrinsic growth capacity. In this report, we studied the role of glycogen synthase kinase-3 (GSK-3) inactivation on neurite and axon growth from adult neurons via combined in vitro and in vivo approaches. We found that the major CNS inhibiting substrates including chondroitin sulfate proteoglycans could inactivate protein kinase B (Akt) and activate GSK-3β signals in neurons. GSK-3 inactivation with pharmacologic inhibitors enhances neurite outgrowth of dorsal root ganglion neurons derived from adult mice or cerebellar granule neurons from postnatal rodents cultured on CNS inhibitors. Application of GSK-3 inhibitors stimulates axon formation and elongation of mature neurons whether in presence or absence of inhibitory substrates. Systemic application of the GSK-3 inhibitor lithium to spinal cord-lesioned rats suppresses the activity of this kinase around lesion. Treatments with GSK-3 inhibitors including a clinical dose of lithium to rats with thoracic spinal cord transection or contusion injuries induce significant descending corticospinal and serotonergic axon sprouting in caudal spinal cord and promote locomotor functional recovery. Our studies suggest that GSK-3 signal is an important therapeutic target for promoting functional recovery of adult CNS injuries and that administration of GSK-3 inhibitors may facilitate the development of an effective treatment to white matter injuries including spinal cord trauma given the wide use of lithium in humans.

Key words: axon growth; regeneration; spinal cord injury; GSK-3β; myelin; chondroitin sulfate proteoglycans

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Received March 18, 2008; revised July 22, 2008; accepted Aug. 1, 2008.

Correspondence should be addressed to Shuxin Li, Department of Neurology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-8813. Email: shuxin.li{at}utsouthwestern.edu

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