Decreased expression of synapse-related genes and loss of synapses in major depressive disorder

Nat Med. 2012 Sep;18(9):1413-7. doi: 10.1038/nm.2886.


Previous imaging and postmortem studies have reported a lower brain volume and a smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of subjects with major depressive disorder (MDD). These findings suggest that synapse number and function are decreased in the dlPFC of patients with MDD. However, there has been no direct evidence reported for synapse loss in MDD, and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function–related genes (CALM2, SYN1, RAB3A, RAB4B and TUBB4) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD and that, when expressed in PFC neurons, is sufficient to decrease the expression of synapse-related genes, cause loss of dendritic spines and dendrites, and produce depressive behavior in rat models of depression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Calmodulin / metabolism
  • Cell Line
  • Depressive Disorder, Major / metabolism
  • Depressive Disorder, Major / pathology*
  • GATA1 Transcription Factor / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation / physiology*
  • Humans
  • Microarray Analysis
  • Microscopy, Electron
  • Prefrontal Cortex / pathology*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Synapses / metabolism
  • Synapses / pathology*
  • Synapsins / metabolism
  • Tubulin / metabolism
  • rab3A GTP-Binding Protein / metabolism
  • rab4 GTP-Binding Proteins / metabolism


  • CALM2 protein, human
  • Calmodulin
  • GATA1 Transcription Factor
  • Synapsins
  • Tubulin
  • rab3A GTP-Binding Protein
  • rab4 GTP-Binding Proteins