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

• Published in: Nature medicine Vol. 18; no. 9; pp. 1413 - 1417
• Main Authors: Kang, Hyo Jung, Voleti, Bhavya, Hajszan, Tibor, Rajkowska, Grazyna, Stockmeier, Craig A, Licznerski, Pawel, Lepack, Ashley, Majik, Mahesh S, Jeong, Lak Shin, Banasr, Mounira, Son, Hyeon, Duman, Ronald S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2012; Nature Publishing Group
• Subjects: 631/378/340; 692/699/476/1414; Analysis of Variance; Animals; Biomedical and Life Sciences; Biomedicine; Calmodulin - metabolism; Cancer Research; Cell Line; Dendrites; Depressive Disorder, Major - metabolism; Depressive Disorder, Major - pathology; GATA1 Transcription Factor - metabolism; Gene expression; Gene Expression Profiling; Gene Expression Regulation - physiology; Humans; Infectious Diseases; letter; Mental depression; Metabolic Diseases; Microarray Analysis; Microscopy, Electron; Molecular Medicine; Neurons; Neurosciences; Polymerase chain reaction; Prefrontal Cortex - pathology; rab3A GTP-Binding Protein - metabolism; rab4 GTP-Binding Proteins - metabolism; Rats; Reverse Transcriptase Polymerase Chain Reaction; Synapses - metabolism; Synapses - pathology; Synapsins - metabolism; Tubulin - metabolism
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2886

Ronald Duman and colleagues report that synapse number is reduced in subjects with major depressive disorder. This is associated with decreased expression of synapse-related genes and increased expression of the transcriptional repressor, GATA1. Expression of GATA1 in prefrontal cortex neurons decreases the expression of synapse-related genes, reduces dendrite branching and produces depressive behavior in a rat model of depression. 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) 1 , 2 . 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.