Journal Article

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

Wong, J, Weickert, C S, Sinclair, D, Webster, M J

2011

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/2571 / 631/45/612/388 / 692/699/476 / Adolescent / Adolescents / Adult / Adult and adolescent clinical studies / Astrocytes / Behavioral Sciences / Biological and medical sciences / Biological Psychology / Bipolar disorder / Brain research / Cerebral Cortex - growth & development / Cerebral Cortex - metabolism / Child / Child development / Child, Preschool / Developmental stages / Female / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Developmental - physiology / Genes / Genetic aspects / Glial Fibrillary Acidic Protein - metabolism / Glucocorticoids / Hormone receptors / Humans / Infant / Life span / Ligands / Localization / Male / Medical research / Medical sciences / Medicine / Medicine & Public Health / Mental depression / Mental disorders / Mental illness / Middle Aged / Molecular Weight / Neonates / Neurosciences / Nonlinear Dynamics / Oligonucleotide Array Sequence Analysis / original-article / Pathogenesis / Pharmacotherapy / Phosphopyruvate Hydratase - metabolism / Physiological aspects / Prefrontal cortex / Protein expression / Proteins / Psychiatry / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Psychoses / Pyramidal cells / Receptors, Glucocorticoid - genetics / Receptors, Glucocorticoid - metabolism / Research centers / Risk factors / RNA, Messenger - metabolism / Schizophrenia / Substantia alba / Western blotting / Young Adult / Young adults