Spine synapse remodeling in the pathophysiology and treatment of depression

Neurosci Lett. 2015 Aug 5:601:20-9. doi: 10.1016/j.neulet.2015.01.022. Epub 2015 Jan 9.


Clinical brain imaging and postmortem studies provide evidence of structural and functional abnormalities of key limbic and cortical structures in depressed patients, suggesting that spine synapse connectivity is altered in depression. Characterization of the cellular determinants underlying these changes in patients are limited, but studies in rodent models demonstrate alterations of dendrite complexity and spine density and function that could contribute to the morphological and functional alterations observed in humans. Rodent studies demonstrate region specific effects in chronic stress models of depression, including reductions in dendrite complexity and spine density in the hippocampus and prefrontal cortex (PFC) but increases in the basolateral amygdala and nucleus accumbens. Alterations of spine synapse connectivity in these regions are thought to contribute to the behavioral symptoms of depression, including disruption of cognition, mood, emotion, motivation, and reward. Studies of the mechanisms underlying these effects demonstrate a role for altered brain derived neurotrophic factor (BDNF) signaling that regulates synaptic protein synthesis. In contrast, there is evidence that chronic antidepressant treatment can block or reverse the spine synapse alterations caused by stress. Notably, the new fast acting antidepressant ketamine, which produces rapid therapeutic actions in treatment resistant MDD patients, rapidly increases spine synapse number in the PFC of rodents and reverses the effects of chronic stress. The rapid synaptic and behavioral actions of ketamine occur via increased BDNF regulation of synaptic protein synthesis. Together these studies provide evidence for a neurotophic and synaptogenic hypothesis of depression and treatment response and indicate that spine synapse connectivity in key cortical and limbic brain regions is critical for control of mood and emotion.

Keywords: Antidepressant; Glutamate; Ketamine; Neurotrophic factor; Stress.

Publication types

  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / therapeutic use
  • Cerebral Cortex / pathology
  • Cerebral Cortex / physiopathology
  • Dendritic Spines / physiology*
  • Dendritic Spines / ultrastructure
  • Depression / drug therapy
  • Depression / etiology
  • Depression / pathology
  • Depression / physiopathology*
  • Humans
  • Limbic System / pathology
  • Limbic System / physiopathology
  • Neurons / pathology
  • Stress, Psychological / complications
  • Stress, Psychological / pathology
  • Stress, Psychological / physiopathology
  • Synapses / physiology*


  • Antidepressive Agents