Background & Objective: Ketamine, a noncompetitive NMDA receptor antagonist, exhibits
rapid antidepressant actions, but the underlying mechanism remains obscure. AMPA receptor and
cAMP response element-binding protein (CREB) are involved in the antidepressant actions of Ketamine
and imipramine, a traditional tricyclic antidepressant. However, ketamine exerts its therapeutic
actions much faster than imipramine. Understanding the discrepancy of antidepressant efficiency between
ketamine and the traditional antidepressant is important for elucidating the mechanism underlying
ketamine’s fast-acting antidepressant responses as well as designing new rapid antidepressants.
Results: Here we show that the enhancement of the phosphorylation of CREB Ser133 and expression
of CREB and glutamate receptor 1 (GluR1) are necessary for both ketamine’s and imipramine's antidepressant
actions, but the enhancements at early stage may account for the faster onset of ketamine's
antidepressant action than imipramine. Notably, ketamine but not imipramine enhances CREBregulated
transcription coactivator-1 (CRTC1) expression and induces potentiation of excitatory synaptic
transmission at Schaffer collateral CA1 synapses, which indicates critical targets for unveiling
ketamine's rapid antidepressant actions.
Conclusion: Our study suggests that differential regulation of CRTC1 expression may contribute to
the discrepancy of antidepressant efficacy between ketamine and imipramine, which may lead to a better
understanding of ketamine's fast antidepressant responses.