Fig. 1.

Rapid antidepressant mechanism of ketamine in medial prefrontal cortex. Repeated stress causes a malfunction of synaptic connectivity, characterized by decreases in glutamate release and AMPAR function, signal transduction, and synaptic protein synthesis, resulting in decreased number and function of spine synapses. Ketamine treatment is thought to cause disinhibition of GABAergic interneurons through blockade of NMDARs, resulting in widespread bursts of glutamate release in the medial prefrontal cortex. Glutamate release further activates AMPARs, contributing to BDNF release and the activation of a series of downstream pathways such as mTORC1 signaling, which increases synaptic protein synthesis and AMPAR trafficking. This widespread activation of signaling pathways leads to synapse recovery and regeneration, and thus remission of the depressed state.