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Trends Neurosci. 2015 May;38(5):279-94. doi: 10.1016/j.tins.2015.03.003. Epub 2015 Apr 14.

An excitatory synapse hypothesis of depression.

Author information

1
Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Department of Psychiatry, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA. Electronic address: sthom003@umaryland.edu.
2
Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.
3
Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Medical Scientist Training Program, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.
4
Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.
5
Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA; Department of Physiology, Southern Illinois University, Carbondale, IL 62901, USA.

Abstract

Depression is a common cause of mortality and morbidity, but the biological bases of the deficits in emotional and cognitive processing remain incompletely understood. Current antidepressant therapies are effective in only some patients and act slowly. Here, we propose an excitatory synapse hypothesis of depression in which chronic stress and genetic susceptibility cause changes in the strength of subsets of glutamatergic synapses at multiple locations, including the prefrontal cortex (PFC), hippocampus, and nucleus accumbens (NAc), leading to a dysfunction of corticomesolimbic reward circuitry that underlies many of the symptoms of depression. This hypothesis accounts for current depression treatments and suggests an updated framework for the development of better therapeutic compounds.

KEYWORDS:

glutamate; hippocampus; ketamine; nucleus accumbens; reward; stress

PMID:
25887240
PMCID:
PMC4417609
DOI:
10.1016/j.tins.2015.03.003
[Indexed for MEDLINE]
Free PMC Article

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