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.
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This work is supported by US Public Health Service grants MH45481 (R.S.D.), 2 P01 MH25642 (R.S.D.), MH67996 (C.A.S.) and P20 RR17701 (C.A.S.), the Connecticut Mental Health Center (R.S.D.) and a National Research Foundation of Korea grant (NRF, 2011-0028317; H.S.). We acknowledge the invaluable contributions made by the families consenting to donate brain tissue and be interviewed. We also thank the Cuyahoga County Coroner and staff, Cleveland, Ohio, for their willing assistance. We thank J. Overholser, G. Jurjus, H. Meltzer, L. Konick, L. Dieter, N. Herbst, G. Mahajan, H. Kooiman and J. Cobb for their contributions to the psychiatric assessment and human tissue dissection and preparation. We thank T.H. Kim (Yale University) for his advice and suggestions regarding the binding motif analysis and chromatin immunoprecipitation. The pXM-GATA1 plasmid was provided by A.B. Cantor (Harvard University), and the pAAV-eGFP-pA vector was provided by R.J. Dileone (Yale University). The GATA1-specific antibody was provided by E.H. Bresnick (University of Wisconsin).
The authors declare no competing financial interests.
Supplementary Figures 1–7 (PDF 515 kb)
Synaptic enriched genes were decreased in MDD (XLS 28 kb)
TRANSFAC MATRIX of the synapse related genes_Human (XLS 6368 kb)
TRNASFAC MATRIX of the synapse related genes_Rat (XLS 4874 kb)
List of PCR primers used in this study for validation (XLS 33 kb)
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Kang, H., Voleti, B., Hajszan, T. et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 18, 1413–1417 (2012). https://doi.org/10.1038/nm.2886
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