Signaling pathways underlying the rapid antidepressant actions of ketamine

Abstract

Currently available medications have significant limitations, most notably low response rate and time lag for treatment response. Recent clinical studies have demonstrated that ketamine, an NMDA receptor antagonist produces a rapid antidepressant response (within hours) and is effective in treatment resistant depressed patients. Molecular and cellular studies in rodent models demonstrate that ketamine rapidly increases synaptogenesis, including increased density and function of spine synapses, in the prefrontal cortex (PFC). Ketamine also produces rapid antidepressant actions in behavioral models of depression, and reverses the deficits in synapse number and behavior resulting from chronic stress exposure. These effects of ketamine are accompanied by stimulation of the mammalian target of rapamycin (mTOR), and increased levels of synaptic proteins. Together these studies indicate that ketamine rapidly reverses the atrophy of spines in the PFC and thereby causes a functional reconnection of neurons that underlies the rapid behavioral responses. These findings identify new targets for rapid acting antidepressants that are safer than ketamine. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Figure 1

Model for activity-dependent induction of mature spines. Diagram shows a presynaptic terminal with synaptic vesicle adjacent to an immature spine. Synaptic activity leads to spine maturation and insertion of glutamate AMPA receptors into the postsynaptic membrane. The signaling mechanisms underlying synaptogenesis are studied in a cellular model of learning and memory, long- term potentiation (LTP). See text for details.

Figure 2

Ketamine stimulates mTOR and synaptogenesis: neurotransmitter and intracellular signaling mechanisms. Ketamine stimulates glutamate transmission, resulting in BDNF release and activation of Akt and ERK signaling, which in turn stimulate mTOR and synaptic protein synthesis. This leads to insertion of GluR1 and increased synaptogenesis, which contributes to the rapid antidepressant effects of ketamine. See text for details.

Figure 3

Targets for induction of synaptogenesis and ketamine-like effects. Potential targets that could produce ketamine like effects include presynaptic mGlu2/3 receptor antagonists and postsynaptic positive AMPA receptor potentiating agents. Both would lead to increased glutamate transmission and AMPA receptor activation, and thereby stimulate mTOR signaling and increase synaptogenesis. See text for details.