GSK3 Function in the Brain during Development, Neuronal Plasticity, and Neurodegeneration

Figure 3

Schematic representation of pre- and postsynaptic mechanisms involved in neuronal plasticity and the role of GSK3. In the presynapse GSK3 activity decreases the expression of SynI reducing the release of glutamate while in postsynapses GSK3 transiently activates NMDA receptors leading to endocytosis of AMPA receptors and reduces the levels of PSD93 protein, favoring LTD. In contrast, Wnt and PI3K signaling pathways or pharmacological inhibition of GSK3 by LiCl supports the induction of LTP, facilitating learning and memory. GSK3 inhibition is also involved in axon and dendritic widening in both pre- and postsynaptic sites. Serine/threonine phosphatases PP1 and PP2A can activate GSK3 regulating phosphor-GSK3 levels through its dephosphorylation. GSK3 is important in the modulation of multiple signaling pathways including Notch pathway that plays an important role in different developmental processes. In AD, amyloid-β oligomers inhibit Wnt and insulin signaling pathways leading to activation of GSK3. In addition, GSK3 overactivation mediates 𝜏 hyperphosphorylation and microtubule destabilization.