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

Abstract

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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Figure 1: Synaptic-function–related genes, the number of spine synapses and MAP2 expression are decreased in the dlPFC of subjects with MDD.
Figure 2: Identification of GATA1 as a transcriptional repressor of synapse-related genes.
Figure 3: GATA1 overexpression in cortical neurons decreases Rab4b expression and reduces dendrite branching.
Figure 4: Viral expression of GATA1 in rat PFCs causes depressive behavior.

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Acknowledgements

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).

Author information

Authors and Affiliations

Authors

Contributions

H.J.K. was involved in planning and conducting all aspects of the research, including the analysis of microarray data, the confirmation of results, the molecular and cellular experiments and the construction of the viral vectors; H.J.K. also prepared the first draft of the manuscript. B.V. designed viral vectors, conducted the behavioral studies and was involved in the analysis and interpretation of rodent behavioral studies. C.A.S. and G.R. were responsible for the generation of tables containing the relevant information from the human subjects and the corresponding methodology and for preparation of human tissue and microdissections. T.H. conducted electron microscopy analysis of synapse number in postmortem tissue. M.B., with the technical help of A.L., carried out the rat CUS studies and prepared tissues for in situ hybridization analysis, surgeries for viral infusion in rats and supervised behavioral studies. P.L. was involved in the viral vector preparations. H.S. was involved in viral vector experiments, including surgical infusions, behavioral studies and immunohistochemistry. M.S.M. and L.S.J. synthesized the GATA1-specific inhibitor, K-7174. R.S.D. was responsible for overseeing the study, including all aspects of study design, data analysis, interpretation of results and preparation of the manuscript and figures. All authors discussed the results presented in the manuscript.

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Correspondence to Ronald S Duman.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 515 kb)

Supplementary Table 1

Synaptic enriched genes were decreased in MDD (XLS 28 kb)

Supplementary Table 2

TRANSFAC MATRIX of the synapse related genes_Human (XLS 6368 kb)

Supplementary Table 3

TRNASFAC MATRIX of the synapse related genes_Rat (XLS 4874 kb)

Supplementary Table 4

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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