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Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development

Citation

Sinclair, D and Webster, MJ and Wong, J and Weickert, CS, Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development, Molecular Psychiatry, 16, (5) pp. 504-515. ISSN 1359-4184 (2011) [Refereed Article]

Copyright Statement

Copyright 2011 Macmillan Publishers Limited

DOI: doi:10.1038/mp.2010.28

Abstract

The glucocorticoid receptor (GR) has a critical role in determining the brain's capacity to respond to stress, and has been implicated in the pathogenesis of psychiatric illness. We hypothesized that key changes in cortical GR occur during adolescence and young adulthood, at a time when individuals are at increased risk of developing schizophrenia, bipolar disorder and major depression. We investigated the mRNA and protein expression of GR in the dorsolateral prefrontal cortex across seven developmental time points from infancy to adulthood. GR mRNA expression, determined by microarray and quantitative real-time PCR, was lowest in neonates and peaked around young adulthood. Western blotting revealed two dynamic patterns of GRα protein expression across the lifespan, with N-terminal variants displaying differing unique patterns of abundance. GRα-A and a 67-kDa GRα isoform mirrored mRNA trends and peaked in toddlers and late in adolescence, whereas a 40-kDa isoform, very likely a GRα-D variant, peaked in neonates and decreased across the lifespan. GRα protein was localized to pyramidal neurons throughout life and most strikingly in young adulthood, but to white matter astrocytes only in neonates and infants (<130 days). These results suggest that the neonatal and late adolescent periods represent critical windows of stress pathway development, and highlight the importance of white matter astrocytes and pyramidal neurons, respectively, at these stages of cortical development. Evidence of dynamic patterns of GR isoform expression and cellular localization across development strengthens the hypothesis that windows of vulnerability to stress exist across human cortical development.

Item Details

Item Type:Refereed Article
Keywords:stress, glucocorticoid, brain development
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Cellular Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
UTAS Author:Sinclair, D (Dr Duncan Sinclair)
ID Code:130638
Year Published:2011
Web of Science® Times Cited:42
Deposited By:Wicking Dementia Research and Education Centre
Deposited On:2019-02-06
Last Modified:2019-05-23
Downloads:0

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