GSK-3 β at the Intersection of Neuronal Plasticity and Neurodegeneration

Abstract

In neurons, Glycogen Synthase Kinase-3β (GSK-3β) has been shown to regulate various critical processes underlying structural and functional synaptic plasticity. Mouse models with neuron-selective expression or deletion of GSK-3β present behavioral and cognitive abnormalities, positioning this protein kinase as a key signaling molecule in normal brain functioning. Furthermore, mouse models with defective GSK-3β activity display distinct structural and behavioral abnormalities, which model some aspects of different neurological and neuropsychiatric disorders. Equalizing GSK-3β activity in these mouse models by genetic or pharmacological interventions is able to rescue some of these abnormalities. Thus, GSK-3β is a relevant therapeutic target for the treatment of many brain disorders. Here, we provide an overview of how GSK-3β is regulated in physiological synaptic plasticity and how aberrant GSK-3β activity contributes to the development of dysfunctional synaptic plasticity in neuropsychiatric and neurodegenerative disorders.

Figure 1

Molecular mechanisms of GSK-3β regulation. (a) The Wnt canonical pathway. In the absence of Wnt, β-catenin is degraded within a destruction complex composed of Axin, APC, and GSK-3β proteins. Following Wnt binding to Frizzled and LRP5/6 receptors, Dvl is recruited resulting in the sequestration of the destruction complex within the MVB. This allows β-catenin to accumulate, translocate to the nucleus, and subsequently induce gene expression via the TCF/LEF transcription factors. (b) The PI3K/Akt pathway. The activation of PI3K following the stimulation of Tyrosine Kinase Receptor leads to the production of PIP3. Akt kinase is recruited and is activated upon phosphorylation at Thr308 and Ser473 by PDK1 and mTORC2, respectively. The signal is terminated following PIP3 dephosphorylation by PTEN phosphatase. Akt kinase phosphorylates and inhibits GSK-3β activity by a reversible phosphorylation at Ser9. An incomplete list of the GSK-3β substrates and cellular processes that it regulates is shown.

Figure 2

GSK-3β at glutamatergic synapse. (a) Role of GSK-3β in the structural plasticity of glutamatergic synapse. (Left) Under normal conditions, synapse function is maintained by homeostatic mechanisms that depend on the cycling of glutamate receptors within the synapse. Transient changes in GSK-3β activity will support molecular mechanisms required for these processes. (Middle) Synaptic destabilization following LTD or chronic stress decreases synaptic density and causes synapse atrophy. High GSK-3β activity is required for pre- and postsynaptic molecular mechanisms to support the occurrence of LTD. Increased GSK-3β activity has been reported in different neurological and neuropsychiatric disorders. (Right) Following LTP stimuli, GSK-3β is inhibited to enable synaptic growth. LTP stimuli also increase BDNF and Wnt proteins which act to inhibit GSK-3β during LTP. (b) GSK-3β determines the direction of NMDA receptor-mediated plasticity. (Right) During LTD, activation of PP1 causes dephosphorylation and thus activation of GSK-3β by the Ser9 mechanism. Simultaneously, active PP1 inhibits Akt preventing Ser9 phosphorylation of GSK-3β. During LTP, the activation of NMDA receptors stimulates the PI3K-Akt pathway, which phosphorylates and inhibits GSK-3β activity to prevent the induction of LTD.