Overexpression of human GATA-1 and GATA-2 interferes with spine formation and produces depressive behavior in rats.

Miyeon Choi,Ronald S Duman,Hyo Jung Kang,Hyeon Son,Seung Yeon Ko,Seung Hoon Lee,Sung Eun Wang,Seung Yeun Chae,Yong-Seok Kim,Shashank M Dravid

doi:10.1371/journal.pone.0109253

Miyeon Choi, Ronald S Duman + Show 8 more

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https://doi.org/10.1371/journal.pone.0109253

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Journal: PloS one	Publication Date: Oct 23, 2014
Citations: 20	License type: CC BY 4.0

Affiliation: Yale University, Chung-Ang University, Hanyang University

Abstract

Functional consequences to which vertebrate GATA transcription factors contribute in the adult brain remain largely an open question. The present study examines how human GATA-1 and GATA-2 (hGATA-1 and hGATA-2) are linked to neuronal differentiation and depressive behaviors in rats. We investigated the effects of adeno-associated viral expression of hGATA-1 and hGATA-2 (AAV-hGATA1 and AAV-hGATA2) in the dentate gyrus (DG) of the dorsal hippocampus on dendrite branching and spine number. We also examined the influence of AAV-hGATA1 and AAV-hGATA2 infusions into the dorsal hippocampus on rodent behavior in models of depression. Viral expression of hGATA-1 and hGATA-2 cDNA in rat hippocampal neurons impaired dendritic outgrowth and spine formation. Moreover, viral-mediated expression of hGATA-1 and hGATA-2 in the dorsal hippocampus caused depressive-like deficits in the forced swim test and learned helplessness models of depression, and decreased the expression of several synapse-related genes as well as spine number in hippocampal neurons. Conversely, shRNA knockdown of GATA-2 increased synapse-related gene expression, spine number, and dendrite branching. The results demonstrate that hGATA-1 and hGATA-2 expression in hippocampus is sufficient to cause depressive like behaviors that are associated with reduction in spine synapse density and expression of synapse-related genes.

Highlights

There is a rich cross-talk between transcription factors and signaling pathways that regulate neuronal growth and synapse formation [1,2], and there is extensive evidence that changes in spine morphology couple with synaptic function in neurons [3]
Since the involvement of GATA-2 in cellular and behavioral abnormalities related to stress and depression remains an open question, we investigated the influence of acute and chronic stress on the expression levels of rGATA-2 mRNA in the hippocampus
We show that viral expression of hGATA-1 or hGATA-2 transcription factors suppress the expression of genes that are involved in spine formation and neurite outgrowth in the rat hippocampal cells

Summary

Introduction

There is a rich cross-talk between transcription factors and signaling pathways that regulate neuronal growth and synapse formation [1,2], and there is extensive evidence that changes in spine morphology couple with synaptic function in neurons [3]. These functional and structural changes in dendritic spines are thought to be the basis for learning and memory in the brain [4,5]. GATA-1 was shown to exert repressive effects on spine formation in rat cortical neurons [10] and has been implicated in major depressive disorder (MDD) based on evidence that GATA-1 levels are increased postmortem prefrontal cortex and hippocampus of MDD subjects [11]

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