Neurobiology of stress, depression, and rapid acting antidepressants: remodeling synaptic connections

Abstract

Stress and depression are associated with atrophy and loss of neurons in limbic and cortical brain regions that could contribute to the symptoms of depression. Typical monoamine reuptake inhibitor antidepressants have only modest efficacy and require long-term treatment, and are only weakly effective in blocking or reversing these structural changes caused by stress. Recent findings demonstrate that ketamine, an NMDA receptor antagonist, produces rapid antidepressant actions in difficult to treat depressed patients. In addition, preclinical studies demonstrate that ketamine rapidly increases synaptic connections in the prefrontal cortex by increasing glutamate signaling and activation of pathways that control the synthesis of synaptic proteins. Moreover, ketamine rapidly reverses the synaptic deficits caused by exposure to chronic stress in rodent models. Studies of the signaling mechanisms underlying the actions of ketamine have provided novel approaches and targets for new rapid acting antidepressants with decreased side effects, as well as a better understanding of the neurobiology of stress, depression, and treatment response.

Keywords: Scopolamine; brain-derived neurotrophic factor; glycogen synthase kinase-3; lithium; mechanistic target of rapamycin.

Figure 1

Model for the loss of synapses caused by stress and rapid induction of synaptic connections by ketamine. Synaptic connections in the PFC are maintained by normal circuit activity, but are decreased by chronic stress exposure, which also reduces the expression of BDNF. Ketamine can rapidly reverse the effects of stress by causing a burst of glutamate that causes a fast synaptogenic response. This is thought to occur via blockade of tonic firing GABAergic interneurons that express NMDA receptors. Ketamine induction of synapses requires BDNF and activation of the mTOR signaling pathway, which regulates the synthesis of new synaptic proteins, including glutamate AMPA receptors. The cycling of AMPA receptors to the membrane is also regulated by GSK-3β, a target of lithium that has been implicated in the actions of ketamine. Although relatively stable, the new synapses reverse after 7–10 days, consistent with the time course for relapse of depressed patients after a single dose of ketamine. The effects of stress on synaptic connections can also be influenced by exercise, enriched environment, and coping mechanisms.