An excitatory synapse hypothesis of depression

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Brain / pathology
  • Depression / drug therapy
  • Depression / pathology*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology*
  • Humans
  • Synapses / drug effects
  • Synapses / physiology*


  • Antidepressive Agents