Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS

John Dill, Hongyu Wang, Fengquan Zhou, Shuxin Li

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8914-8928
Number of pages15
JournalJournal of Neuroscience
Volume28
Issue number36
DOIs
StatePublished - Sep 3 2008

Keywords

  • Axon growth
  • Chondroitin sulfate proteoglycans
  • GSK-3β
  • Myelin
  • Regeneration
  • Spinal cord injury

ASJC Scopus subject areas

  • Neuroscience(all)

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