In the past decade, studies that provide insights into the mechanisms of action underlying ketamine’s rapid antidepressant effects have been key to identifying relevant targets for developing novel antidepressants with rapid and sustained effects1. In this context, glycogen synthase kinase 3 (GSK-3) appears to be a top candidate. GSK-3 has been extensively associated with mood disorders, particularly with regard to lithium’s effects on this target and the potential association with clinical improvement2–4. GSK-3 also plays a key role in relevant biological processes such as oxidative stress, neurogenesis, and inflammation3.

In an elegant preclinical study, Beurel and colleagues5 recently demonstrated an integrated functional effect between GSK-3 and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in ketamine’s rapid antidepressant effects. Specifically, the study found that ketamine-induced GSK-3 inhibition upregulated AMPA GluA1 subunits and stabilized AMPA receptors at the cell surface. Ketamine also decreased post-synaptic density 95 (PSD-95) phosphorylation; PSD-95 is a known substrate for GSK-3 that directly regulates the number of AMPA receptors at the cell surface and, consequently, regulates synaptic strength6. Notably, the limiting effects at PSD-95 led to lower internalization of AMPA GluA1, which also had a central regulatory effect on AMPA receptor trafficking5. It is important to note that GSK-3 was previously shown to regulate AMPA receptor trafficking7 and is also associated with PSD-95 phosphorylation8. These recent findings by Beurel and colleagues underscore the relevance of GSK-3 and postsynaptic density proteins in ketamine’s rapid antidepressant effects.