A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

Stress and antidepressant treatments have opposing effects on neurotrophic factors like brain-derived neurotrophic factor in brain regions such as the hippocampus and prefrontal cortex (PFC). Stress reduces these factors, leading to decreased neurogenesis, dendrite length, and spine density, which may contribute to the reduced brain volume seen in depressed patients. Antidepressant treatments can block or reverse this atrophy. A novel rapid-acting antidepressant, ketamine, an NMDA receptor antagonist, rapidly induces synaptogenesis and spine formation in the PFC by stimulating the mammalian target of the rapamycin signaling pathway and increasing synaptic protein synthesis. These effects reverse chronic stress-induced PFC neuron atrophy and correspond to rapid behavioral actions in depression models, identifying new cellular targets for rapid antidepressant actions without ketamine's side effects.

Study at a glance

Abstract

Molecular and cellular studies have demonstrated opposing actions of stress and antidepressant treatment on the expression of neurotrophic factors, particularly brain-derived neurotrophic factor, in limbic structures of the brain. These changes in neurotrophic factor expression and function result in structural alterations, including regulation of neurogenesis, dendrite length and spine density in hippocampus and prefrontal cortex (PFC). The deleterious effects of stress could contribute to the reduced volume of these brain regions in depressed patients. Conversely, the actions of antidepressant treatment could be mediated in part by blocking or reversing the atrophy caused by stress and depression. Recent studies have identified a novel, rapid-acting antidepressant, ketamine, in treatment-resistant depressed patients that addresses the limitations of currently available agents (i.e. delayed onset of action and low response rates). We have found that ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, causes a rapid induction of synaptogenesis and spine formation in the PFC via stimulation of the mammalian target of the rapamycin signalling pathway and increased synthesis of synaptic proteins. These effects of ketamine rapidly reverse the atrophy of PFC neurons caused by chronic stress and correspond to rapid behavioural actions of ketamine in models of depression. Characterization of a novel signalling pathway also identifies new cellular targets that could result in rapid and efficacious antidepressant actions without the side effects of ketamine.