GSK-3β 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.

GSK-3β disrupts neural oscillatory function to inhibit learning and memory in rats

“…Our findings showing GSK-3β-induced increases in theta and gamma spectral power are consistent with previous clinical reports examining oscillatory dysfunction in AD and schizophrenia, two disorders of cognitive dysfunction that also present with increased expression and activity of HIP and/or cortical GSK-3β [2][3][4]. For example, electroencephalogram (EEG) studies revealed that persons with AD or schizophrenia exhibit increased global theta power [47,48] and enhanced resting state and evoked gamma power has been reported for both disorders [49][50][51][52], with increased high gamma activity in schizophrenia inversely associated with cognitive performance both in patients and their first-degree relatives [51].…”

“…Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase with over 100 biological substrates [1] that has been repeatedly shown to play a critical role in the pathology of various neuropsychiatric and neurodegenerative diseases, and in particular those that present with cognitive dysfunction [2][3][4][5]. Whereas decreased GSK-3β activity has been implicated in autism [6][7][8], most often disorders of cognitive dysfunction are associated with increased activation of the kinase, the most widely studied being Alzheimer's disease (AD) [2,9,10].…”

Preventive Electroacupuncture Ameliorates D‐Galactose‐Induced Alzheimer’s Disease‐Like Pathology and Memory Deficits Probably via Inhibition of GSK3β/mTOR Signaling Pathway

“…As discussed in previous reviews [19,51,76], GSK3β functions in the assembly and disassembly of synapses determining synaptic plasticity. Except for the wide-recognized role in the regulation of tau phosphorylation, GSK3β activity also participated in proper synaptic development [77,78] and neurotransmission [79,80].…”

Differential expression of glycogen synthase kinase 3α and 3β isomers in brain cortex of mice following high doses of glucose

“…Accumulating evidences argue that GSK-3, particularly β isomer, is implicated in cell loss through decreasing the threshold for the opening of the mitochondrial mega channel (Yang et al, 2017). At the same time, many studies demonstrated the involvement of GSK-3β in several NDD (Jaworski et al, 2019;Thomas et al, 2013;Matsunaga et al, 2019;Shahab et al, 2014;Sulaiman et al, 2019).…”