GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

Abstract

A single dose of the short-acting NMDA antagonist ketamine produces rapid and prolonged antidepressant effects in treatment-resistant patients with major depressive disorder (MDD), which are thought to occur via restoration of synaptic connectivity. However, acute dissociative side effects and eventual fading of antidepressant effects limit widespread clinical use of ketamine. Recent studies in medial prefrontal cortex (mPFC) show that the synaptogenic and antidepressant-like effects of a single standard dose of ketamine in rodents are dependent upon activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway together with inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3), which relieves its inhibitory in influence on mTOR. Here, we found that the synaptogenic and antidepressant-like effects of a single otherwise subthreshold dose of ketamine were potentiated when given together with a single dose of lithium chloride (a nonselective GSK-3 inhibitor) or a preferential GSK-3b inhibitor; these effects included rapid activation of the mTORC1 signaling pathway, increased inhibitory phosphorylation of GSK-3b, increased synaptic spine density/ diameter, increased excitatory postsynaptic currents in mPFC layer V pyramidal neurons, and antidepressant responses that persist for up to 1 week in the forced-swim test model of depression. The results demonstrate that low, subthreshold doses of ketamine combined with lithium or a selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating the pivotal role of the GSK-3 pathway in modulating the synaptogenic and antidepressant responses to ketamine. The possible mitigation by GSK-3 inhibitors of the eventual fading of ketamine's antidepressant effects remains to be explored.

Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions

“…Conversely, the neuronal silencing agent muscimol inhibits the behavioral actions of ketamine, indicating that NMDA receptor blockade at rest is insufficient to produce antidepressant responses, although there are other views (26,27). A role for neuronal activity is further supported by our results demonstrating that in vivo optogenetic stimulation of IL results in rapid and sustained antidepressant behavioral responses that are associated with increased number and function of spine synapses of layer V pyramidal neurons, similar to the actions of ketamine (4,14,28).…”

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…Finally, cortical pyramidal neurons from a mouse line mutant for the neuronally expressed Wnt/β-catenin pathway activator and DISC1 partner Dixdc1 have reduced dendritic spine and excitatory synapse density correlating with phenotypes in the affective domain (behavioral despair) and social domain (reciprocal social interaction); administration of either lithium or a selective GKS3 inhibitor corrects both the neurodevelopmental and behavioral phenotypes in these animals [343]. This supports that a major neurodevelopmental/neuroplastic target of lithium - and of other psychiatric drugs that either directly or indirectly modulate GSK3 - is the formation, stability, and/or turnover of dendritic spines and glutamatergic synapses [325,344,345]. The same study also provided evidence supporting a “goldilocks principle” for Wnt signaling in these processes at the dendritic spine and synapse, showing that either too much or too little signal pathway activation is similarly deleterious [343].…”

“…Lithium can similarly substitute for Mg in other metalloproteins; its relative specificity for GSK3 and a few other enzymes (such as inositol monophosphatase and inositol polyphosphate 1-phosphatase in the phosphoinositide pathway) stems from biophysical idiosyncrasies - the distribution of positive charges, bulky coordinating residues, and solvent accessibility - of the metal-binding pocket in lithium-sensitive metalloproteins [312]. But lithium is far from the only psychiatric drug to impact GSK3: the mood stabilizer/anticonvulsant valproic acid (VPA) [313,314,315], diverse antipsychotics [316,317,318,319,320], antidepressants including tricyclics and selective serotonin reuptake inhibitors [321,322,323,324], as well as the novel acute antidepressant ketamine [325], all modulate GSK3 as one of their many downstream effects. Many orally administrable molecules with specific and selective inhibitory activity on GSK3 are commercially available and have been widely used in basic scientific studies including in live animal models, with little evidence of toxicity [326,327,328,329,330].…”

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

“…The combination of low (subeffective) dose NMDA receptor antagonists (including ketamine) and lithium also has synergistic antidepressant effects on the forced swim test in rodents [Ghasemi et al 2010]. Finally, GSK-3 inhibition by lithium and a selective GSK-3 inhibitor (SB 216763) potentiates the antidepressant, synaptogenic and electrophysiological effects of subthreshold dose (1 mg/kg) ketamine, for example, mTOR activation, increased excitatory postsynaptic currents and dendritic spine morphogenesis [Liu et al 2013].…”