Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition

• An antidepressant dose of ketamine up-regulates IGF2 in mouse hippocampus
• GSK3 inhibition is necessary and sufficient for up-regulation of IGF2
• Ketamine inhibits activated GSK3 and increases IGF2 expression in depressed mice
• IGF siRNA blocks ketamine's antidepressant efficacy in learned helplessness
• IGF2 levels may differentiate resilient and susceptible mice to learned helplessness

An antidepressant dose of the rapidly-acting ketamine inhibits glycogen synthase kinase-3 (GSK3) in mouse hippocampus, and this inhibition is required for the antidepressant effect of ketamine in learned helplessness depression-like behavior. Here we report that treatment with an antidepressant dose of ketamine (10 mg/kg) increased expression of insulin-like growth factor 2 (IGF2) in mouse hippocampus, an effect that required ketamine-induced inhibition of GSK3. Ketamine also inhibited hippocampal GSK3 and increased expression of hippocampal IGF2 in mice when administered after the induction of learned helplessness. Treatment with the specific GSK3 inhibitor L803-mts was sufficient to up-regulate hippocampal IGF2 expression. Administration of IGF2 siRNA reduced ketamine's antidepressant effect in the learned helplessness paradigm. Mice subjected to the learned helplessness paradigm were separated into two groups, those that were resilient (non-depressed) and those that were susceptible (depressed). Non-depressed resilient mice displayed higher expression of IGF2 than susceptible mice. These results indicate that IGF2 contributes to ketamine's antidepressant effect and that IGF2 may confer resilience to depression-like behavior.