Lithium Inhibits GSK3? and Augments GluN2A Receptor Expression in the Prefrontal Cortex.

ABSTRACT: Glycogen synthase kinase 3? (GSK3?) 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 GSK3? and its interaction with ?-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 GSK3? serine 9, an inhibitory phosphorylation site, and decreased ?-catenin ser33/37/thr41 phosphorylation in vitro, indicating GSK3? inhibition and reduced ?-catenin degradation. GluN2A subunit levels were concurrently increased following lithium treatment. Similar alterations were also demonstrated in vivo; lithium administration increased GSK3? serine 9 phosphorylation and GluN2A levels, suggesting a reduced GSK3? 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 GSK3? activity negatively regulates GluN2A expression, likely by mediating upstream ?-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.

SUBMITTER: Monaco SA 

PROVIDER: S-EPMC5799274 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature