Display Settings:

Format

Send to:

Choose Destination
We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2475-84. doi: 10.1098/rstb.2011.0357.

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

Author information

  • 1Department of Psychiatry, Yale University School of Medicine, , 34 Park Street, New Haven, CT 06508, USA. ronald.duman@yale.edu

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.

PMID:
22826346
[PubMed - indexed for MEDLINE]
PMCID:
PMC3405673
Free PMC Article

Images from this publication.See all images (3)Free text

Figure 1.
Figure 2.
Figure 3.
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk