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

Abstract

GSK3 has diverse functions, including an important role in brain pathology. In this paper, we address the primary functions of GSK3 in development and neuroplasticity, which appear to be interrelated and to mediate age-associated neurological diseases. Specifically, GSK3 plays a pivotal role in controlling neuronal progenitor proliferation and establishment of neuronal polarity during development, and the upstream and downstream signals modulating neuronal GSK3 function affect cytoskeletal reorganization and neuroplasticity throughout the lifespan. Modulation of GSK3 in brain areas subserving cognitive function has become a major focus for treating neuropsychiatric and neurodegenerative diseases. As a crucial node that mediates a variety of neuronal processes, GSK3 is proposed to be a therapeutic target for restoration of synaptic functioning and cognition, particularly in Alzheimer's disease.

Figure 1

Modulation of GSK3 activity by phosphorylation. Protein phosphatases 1 and 2A activate GSK3 by removing Ser9/21 phosphorylation. It has also been reported that phosphorylation in tyrosine residues by members of the receptor tyrosine kinase family of cell surface receptors (RTKs) or by autophosphorylation may activate GSK3. On the other hand, signaling networks activate several protein kinases, which may bring about phosphorylation of different residues and inhibition of GSK3.

Figure 2

Canonical Wnt signaling and GSK3 regulation. Wnt activation trough Frizzled receptor (FzR) induces destabilization of the protein complex composed of axin, adenomatous polyposis coli (APC) protein, β-catenin, casein kinase (Ck1), and GSK3, which results in GSK3 inhibition leading to the induction of β-catenin/TCF target gene expression. When Wnt signalling is off the GSK3/axin complex is not inhibited and β-catenin phosphorylated and is degraded by the proteasome machinery.

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.

Figure 4

Proposed model of GSK3 activation by amyloid-β protein in AD. Amyloid-β oligomers bind to the insulin receptor and inhibit PI3K/Akt pathway, and Akt is unable to phosphorylate and inactivate GSK3. Aβ also induces the expression of DKK1, which internalizes LRP6 receptor and inhibits Wnt signaling leading to GSK3 activation. Aβ can bind to Frizzled receptor (FzR) and inactivate Wnt signaling as well. ApoE also inhibits this signaling pathway and activates GSK3. Tau hyperphosphorylation and NFT formation may result from GSK3 overactivation.