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

An antidepressant dose of ketamine (10 mg/kg) increases expression of insulin-like growth factor 2 (IGF2) in mouse hippocampus, an effect requiring ketamine-induced inhibition of glycogen synthase kinase-3 (GSK3). A specific GSK3 inhibitor also up-regulates hippocampal IGF2. Administering IGF2 siRNA reduces ketamine's antidepressant effect in the learned helplessness paradigm. Non-depressed resilient mice display higher IGF2 expression than susceptible depressed mice. These results indicate that IGF2 contributes to ketamine's antidepressant effect and may confer resilience to depression-like behavior.

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Abstract

ABSTRACT 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. HIGHLIGHTSAn antidepressant dose of ketamine up‐regulates IGF2 in mouse hippocampusGSK3 inhibition is necessary and sufficient for up‐regulation of IGF2Ketamine inhibits activated GSK3 and increases IGF2 expression in depressed miceIGF siRNA blocks ketamine's antidepressant efficacy in learned helplessnessIGF2 levels may differentiate resilient and susceptible mice to learned helplessness