Role of Glycogen Synthase Kinase-3β in Neuronal Apoptosis Induced by Trophic Withdrawal

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Abstract
Glycogen synthase kinase-3β (GSK3β) activity is negatively regulated by several signal transduction cascades that protect neurons against apoptosis, including the phosphatidylinositol-3 kinase (PI-3 kinase) pathway. This suggests the interesting possibility that activation of GSK3β may contribute to neuronal apoptosis. Consequently, we evaluated the role of GSK3β in apoptosis in cultured cortical neurons induced by trophic factor withdrawal or by PI-3 kinase inhibition. Neurons were subjected to several apoptotic paradigms, including serum deprivation, serum deprivation combined with exposure to NMDA receptor antagonists, or treatment with PI-3 kinase inhibitors. These treatments all led to stimulation of GSK3β activity in cortical neurons, which preceded the induction of apoptosis. Expression of an inhibitory GSK3β binding protein or a dominant interfering form of GSK3β reduced neuronal apoptosis, suggesting that GSK3β contributes to trophic factor withdrawal-induced apoptosis. Furthermore, overexpression of GSK3β in neurons increased apoptosis, indicating that activation of this enzyme is sufficient to trigger programmed cell death. Although destabilization of β-catenin is an important physiological effect of GSK3β activation, expression of a mutant β-catenin that is not destabilized by GSK3β did not protect against apoptosis. We conclude that inhibition of GSK3β is one of the mechanisms by which PI-3 kinase activation protects neurons from programmed cell death.