Feature Review
An excitatory synapse hypothesis of depression

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Highlights

  • We review evidence of dysfunction of excitatory synapses in reward circuits in depression.

  • We suggest how these defects arise and how they negatively impact circuit function.

  • We review evidence that many antidepressant drugs and treatments reverse these changes.

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.

Section snippets

Major depressive disorder: from a symptom-based description to biological phenotypes

Major depressive disorder (MDD) is one of the most common and costly of neuropsychiatric syndromes, with a lifetime prevalence of 7–12% in men and 20–25% in women, and a multibillion-dollar annual economic burden in the USA 1, 2.

The most tragic consequence of untreated depression is suicide, attempted by as many as 8% of severely depressed patients. According to the Centers for Disease Control and Prevention, nearly half a million patients receive emergency care for suicide attempts each year

The etiology of depression

Despite its high incidence and its socioeconomic impact, the causes of depression remain poorly understood. Depression involves a combination of genetic and epigenetic susceptibility together with environmental risk factors, such as stress, emotional trauma, or traumatic head injury [7], with heritable factors contributing slightly less than half of the risk. Many SNPs and epigenetic differences are linked to increased risk for depression, but no single gene candidate produces a strong enough

Changes in excitatory synapses in depression

A common element linking stress, serotonin, and neurotrophins is their effects on excitatory synaptic transmission [26]. In preclinical studies, there is increasing evidence that chronic stress exerts deleterious effects on excitatory synaptic structure and function in multiple brain regions associated with cognitive and emotional control of reward behaviors that resemble those seen in human depression. Conversely, serotonin and neurotrophins exert an opposing action, generally promoting

Formal statement of the excitatory synapse hypothesis

  • 1.

    Major depression is caused by a weakening of specific subsets of excitatory synapses in multiple brain regions that are critical in the determination of affect and reward. Chronic hyperactivity of the HPA axis in response to excessive stress, known to be an important allostatic risk factor in the gene × environmental axis determining susceptibility to depression, is one potential mediator of these changes. High levels of GRs in cells in these regions contribute to their vulnerability.

  • 2.

    Many of

Therapeutic implications of the excitatory synapse hypothesis

Although the development of SSRIs has improved the treatment of major depression, there is still considerable need for better therapeutic options. Can the excitatory synapse hypothesis account for the actions of existing therapies and point towards new strategies?

Concluding remarks

In conclusion, although there are many important questions that remain (Box 3), there is considerable evidence that dysfunction of excitatory synapses contributes to the pathology of depression and that many effective antidepressants act to restore normal synaptic strength. We recognize that the evidence in support of the hypothesis is far from complete and that the circuits are more complex than we have indicated here. Our intent in formulating this hypothesis is to stimulate further work and

Acknowledgments

We are grateful to Bradley Alger for teaching us the importance of a well formulated hypothesis. We thank our colleagues Mary Kay Lobo, Brian Mathur, Todd Gould, Robert Schwarcz, and T. Chase Francis for their comments on the manuscript. S.M.T. and X.C. were supported by grant R01 MH086828, A.J.K. and A.M.V. were supported by T32 GM008181, M.D.K. was supported by T32 NS063391, and T.A.L. was supported by T32 NS007375.

Glossary

Allostatic load/overload
allostasis is the concept that homeostatic set-points can be differentially regulated to meet different demands in the internal and external environment (e.g., physical or psychological stress). Repeated allostatic adaptation exacts a cost on the brain.
Chronic restraint stress
animals are placed in restraint tubes for several hours daily, repeated over several days (e.g., 4 hours/day for 10–14 days).
Chronic social defeat
animals are typically placed in the home cage of a

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