Abstract
Glycogen synthase kinase 3β (GSK3β) is a highly conserved serine/threonine kinase that has been implicated in both psychiatric and neurodegenerative diseases including schizophrenia, bipolar disorder, and Alzheimer's disease; therefore regulating its activity has become an important strategy for treatment of cognitive impairments in these disorders. This study examines the effects of lithium on GSK3β and its interaction with β-catenin and NMDA receptors within the prefrontal cortex. Lithium, a clinically relevant drug commonly prescribed as a mood stabilizer for psychiatric disorders, significantly increased levels of phosphorylated GSK3β serine 9, an inhibitory phosphorylation site, and decreased β-catenin ser33/37/thr41 phosphorylation in vitro, indicating GSK3β inhibition and reduced β-catenin degradation. GluN2A subunit levels were concurrently increased following lithium treatment. Similar alterations were also demonstrated in vivo; lithium administration increased GSK3β serine 9 phosphorylation and GluN2A levels, suggesting a reduced GSK3β activity and augmented GluN2A expression. Correspondingly, we observed that the amplitudes of evoked GluN2A-mediated excitatory postsynaptic currents in mPFC pyramidal neurons were significantly increased following lithium administration. Our data suggest that GSK3β activity negatively regulates GluN2A expression, likely by mediating upstream β-catenin phosphorylation, in prefrontal cortical neurons. Furthermore, our biochemical and electrophysiological experiments demonstrate that lithium mediates a specific increase in GluN2A subunit expression, ultimately augmenting GluN2A-mediated currents in the prefrontal cortex.
Highlights
Because Glycogen synthase kinase 3β (GSK3β), β-catenin, and NMDARs all localize within dendritic synapses and β-catenin has been reported to interact with both proteins, we investigated whether the GSK3β/β-catenin signaling pathway regulates NMDAR subunits, GluN2A
Regulating GSK3β activity is a promising candidate for alleviating cognitive symptoms associated with psychiatric and neurodegenerative diseases, albeit how current pharmacological agents mediate their beneficial properties remains unclear
We utilized both in vitro and in vivo approaches to test the hypothesis that GSK3β affects the expression of NMDA receptors in prefrontal neurons by affecting β-catenin availability
Summary
Glycogen synthase kinase 3β (GSK3β) plays an important role in both psychiatric and neurodegenerative disorders (Hur and Zhou, 2010; Eldar-Finkelman and Martinez, 2011; King et al, 2014; Beurel et al, 2015), likely due to its importance in synaptic plasticity (Hooper et al, 2007; Peineau et al, 2007, 2009; Zhu et al, 2007; Bradley et al, 2012; Beurel et al, 2015; Xing et al, 2016). The degradation complex consists of five key proteins including: Axin, APC (adenomatous polyposis coli), CK (casein kinase), GSK3β, and β-catenin (Nakamura et al, 1998; Kikuchi, 1999; Kadoya et al, 2000; Hur and Zhou, 2010). In the absence of Wnt, β-catenin is bound to the active degradation complex and phosphorylated by GSK3β. In the presence of Wnt, β-catenin dissociates from the complex, no longer tagged for degradation, and begins to accumulate in the cytoplasm (Nakamura et al, 1998; Kikuchi, 1999; Kadoya et al, 2000; Hur and Zhou, 2010)
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