Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal.

Glycogen synthase kinase-3beta (GSK3beta) 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 GSK3beta may contribute to neuronal apoptosis. Consequently, we evaluated the role of GSK3beta 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 GSK3beta activity in cortical neurons, which preceded the induction of apoptosis. Expression of an inhibitory GSK3beta binding protein or a dominant interfering form of GSK3beta reduced neuronal apoptosis, suggesting that GSK3beta contributes to trophic factor withdrawal-induced apoptosis. Furthermore, overexpression of GSK3beta in neurons increased apoptosis, indicating that activation of this enzyme is sufficient to trigger programmed cell death. Although destabilization of beta-catenin is an important physiological effect of GSK3beta activation, expression of a mutant beta-catenin that is not destabilized by GSK3beta did not protect against apoptosis. We conclude that inhibition of GSK3beta is one of the mechanisms by which PI-3 kinase activation protects neurons from programmed cell death.