Trends in Neurosciences
Feature ReviewAn excitatory synapse hypothesis of depression
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
References (197)
Neurobiology of depression
Neuron
(2002)- et al.
The genetics of major depression
Neuron
(2014) The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease
Neurosci. Biobehav. Rev.
(2005)Allostasis and allostatic load: implications for neuropsychopharmacology
Neuropsychopharmacology
(2000)The corticosteroid receptor hypothesis of depression
Neuropsychopharmacology
(2000)The glucocorticoid receptor: pivot of depression and of antidepressant treatment?
Psychoneuroendocrinology
(2011)- et al.
Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors
Neuroscience
(1995) Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression
J. Affect. Disord.
(2009)Larger amygdala volumes in first depressive episode as compared to recurrent major depression and healthy control subjects
Biol. Psychiatry
(2003)Structural brain abnormalities in major depressive disorder: a selective review of recent MRI studies
J. Affect. Disord.
(2009)
Nucleus accumbens medium spiny neuron subtypes mediate depression–related outcomes to social defeat stress
Biol. Psychiatry
Restoring mood balance in depression: ketamine reverses deficit in dopamine-dependent synaptic plasticity
Biol. Psychiatry
The mesoaccumbens dopamine in coping with stress
Neurosci. Biobehav. Rev.
Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions
Cell
Neuroscience of affect: brain mechanisms of pleasure and displeasure
Curr. Opin. Neurobiol.
Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex
Neuron
Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells
Neuropharmacology
Covariation of activity in habenula and dorsal raphé nuclei following tryptophan depletion
Neuroimage
Amygdala microcircuits controlling learned fear
Neuron
Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors
Neuroscience
Stress-induced changes in messenger RNA levels of N-methyl-D-aspartate and AMPA receptor subunits in selected regions of the rat hippocampus and hypothalamus
Neuroscience
Properties of [3H]AMPA binding in postmortem human brain from psychotic subjects and controls: increases in caudate nucleus associated with suicide
Exp. Neurol.
Striatal ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and major depressive disorder
Brain Res. Bull.
Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study
Biol. Psychiatry
Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients
Psychiatr. Res.
Correlation between plasma levels of glutamate, alanine and serine with severity of depression
Prog. Neuropsychopharmacol. Biol. Psychiatry
The mesolimbic dopamine reward circuit in depression
Biol. Psychiatry
Stress, anxiety, and dendritic spines: what are the connections?
Neuroscience
Anhedonia predicts suicidal ideation in a large psychiatric inpatient sample
Psychiatry Res.
The mysterious motivational functions of mesolimbic dopamine
Neuron
Presynaptic partners of dorsal raphe serotonergic and GABAergic neurons
Neuron
Antidepressant effects of ketamine in depressed patients
Biol. Psychiatry
Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication
Arch. Gen. Psychiatry
Major depressive disorder
N. Engl. J. Med.
Suicide Facts at a Glance
Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review
What did STAR* D teach us? Results from a large-scale, practical, clinical trial for patients with depression
Psychiatr. Serv.
Synaptic dysfunction in depression: potential therapeutic targets
Science
Anna-Monika-Prize paper. Major depression and the environment: a psychiatric genetic perspective
Pharmacopsychiatry
Social–environmental factors in unipolar depression: comparisons of depressed patients and nondepressed controls
J. Abnorm. Psychol.
Why Zebras Don’t Get Ulcers: A Guide to Stress, Stress Related Diseases, and Coping
Risk factors for development of depression and psychosis. Glucocorticoid receptors and pituitary implications for treatment with antidepressant and glucocorticoids
Ann. N. Y. Acad. Sci.
Glucocorticoid sensitivity in mood disorders
Neuroendocrinology
Effects of glucocorticoids on mood, memory, and the hippocampus. Treatment and preventive therapy
Ann. N. Y. Acad. Sci.
A comparison of clinician-rated neuropsychological and self-rated cognitive assessments in patients with asthma and rheumatologic disorders
Allergy asthma Proc.
Brain on stress: how the social environment gets under the skin
Proc. Natl. Acad. Sci. U.S.A.
Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4
J. Neurochem.
Stress, depression, and neuroplasticity: a convergence of mechanisms
Neuropsychopharmacology
Cortico-basal ganglia reward network: microcircuitry
Neuropsychopharmacology
Disentangling pleasure from incentive salience and learning signals in brain reward circuitry
Proc. Natl. Acad. Sci. U.S.A.
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