mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

TLDR

Ketamine produces antidepressant effects within 4–6 hours, a rapid response compared to the weeks or months required for standard antidepressants. The study investigates the mechanisms underlying ketamine’s rapid antidepressant actions. Ketamine rapidly activates mTOR signaling, elevates synaptic protein levels, and increases dendritic spine density and function in the prefrontal cortex, with its antidepressant effects dependent on mTOR activity. Li et al.

Abstract

Antidepressant Action of Ketamine In contrast to the weeks or months of treatment required for standard antidepressant medication, ketamine administration produces an antidepressant response within 4 to 6 hours in depressed patients. What lies behind the rapid actions of ketamine? Li et al. (p. 959 ; see the Perspective by Cryan and O'Leary ) found that ketamine administration resulted in fast activation of mammalian target of rapamycin (mTOR) signaling and increased levels of synaptic proteins in the rat prefrontal cortex. Ketamine rapidly increased the density and function of the dendritic spines of layer V pyramidal neurons in the prefrontal cortex. Thus, the behavioral actions of ketamine in models of depression and antidepressant response are dependent on mTOR signaling.