Glucocorticoid receptor mRNA and protein isoform alterations in the orbitofrontal cortex in schizophrenia and bipolar disorder.
ABSTRACT BACKGROUND: The orbitofrontal cortex (OFC) may play a role in the pathogenesis of psychiatric illnesses such as bipolar disorder and schizophrenia, in which hypothalamic-pituitary-adrenal (HPA) axis abnormalities are observed and stress has been implicated. A critical component of the HPA axis which mediates cellular stress responses in the OFC, and has been implicated in psychiatric illness, is the glucocorticoid receptor (GR). METHODS: In the lateral OFC, we employed quantitative real-time PCR and western blotting to investigate GR mRNA and protein expression in 34 bipolar disorder cases, 35 schizophrenia cases and 35 controls. Genotype data for eleven GR gene (NR3C1) polymorphisms was also used to explore possible effects of NR3C1 sequence variation on GR mRNA and protein expression in the lateral OFC. RESULTS: We found no diagnostic differences in pan GR, GR-1C or GR-1F mRNA expression. However, the GR-1B mRNA transcript variant was decreased (14.3%) in bipolar disorder cases relative to controls (p<0.05), while GR-1H mRNA was decreased (22.0%) in schizophrenia cases relative to controls (p<0.005). By western blotting, there were significant increases in abundance of a truncated GRalpha isoform, putative GRalpha-D1, in bipolar disorder (56.1%, p<0.005) and schizophrenia (31.5% p<0.05). Using genotype data for eleven NR3C1 polymorphisms, we found no evidence of effects of NR3C1 genotype on GR mRNA or GRalpha protein expression in the OFC. CONCLUSIONS: These findings reveal selective abnormalities of GR mRNA expression in the lateral OFC in psychiatric illness, which are more specific and may be less influenced by NR3C1 genotype than those of the dorsolateral prefrontal cortex reported previously. Our results suggest that the GRalpha-D1 protein isoform may be up-regulated widely across the frontal cortex in psychiatric illness.
Article: Alterations in phencyclidine and sigma binding sites in schizophrenic brains. Effects of disease process and neuroleptic medication.[show abstract] [hide abstract]
ABSTRACT: The specific binding of [3H]TCP and [3H](+)3-PPP, radioligands which respectively label PCP-NMDA and sigma binding sites was measured in tissue homogenates prepared from dissected areas of control and schizophrenic postmortem brains. [3H]TCP binding was bilaterally increased in orbital frontal cortex (Brodmann area 11) of schizophrenic brains. This finding may be due to an increased glutamatergic innervation of orbital frontal cortex since it parallels our findings of increased [3H]kainate and [3H]D-aspartate binding in this area. In contrast, [3H](+)3-PPP binding was reduced in each of the four brain regions examined. The reductions were greatest in brains from the schizophrenic subjects receiving neuroleptics at the time of death. Neuroleptics remaining in the brains of these subjects may compete in vitro with [3H](+)3-PPP for binding to the sigma site.Schizophrenia Research 01/1992; 6(1):41-8. · 4.75 Impact Factor
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ABSTRACT: Although cells in many brain regions respond to reward, the cortical-basal ganglia circuit is at the heart of the reward system. The key structures in this network are the anterior cingulate cortex, the orbital prefrontal cortex, the ventral striatum, the ventral pallidum, and the midbrain dopamine neurons. In addition, other structures, including the dorsal prefrontal cortex, amygdala, hippocampus, thalamus, and lateral habenular nucleus, and specific brainstem structures such as the pedunculopontine nucleus, and the raphe nucleus, are key components in regulating the reward circuit. Connectivity between these areas forms a complex neural network that mediates different aspects of reward processing. Advances in neuroimaging techniques allow better spatial and temporal resolution. These studies now demonstrate that human functional and structural imaging results map increasingly close to primate anatomy.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2009; 35(1):4-26. · 6.99 Impact Factor
Article: Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed.[show abstract] [hide abstract]
ABSTRACT: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent findings in major depressive disorder (MDD). Impaired HPA feedback may be due to the lower glucocorticoid receptor (GR) or mineralocorticoid receptor (MR) levels in the forebrain. GR levels are transcriptionally controlled by multiple untranslated alternative first exons, each with its own promoter providing a mechanism for tissue-specific fine-tuning of GR levels. Recently epigenetic methylation of these GR promoters was shown to modulate hippocampal GR levels. Here we investigate in post-mortem brain tissues whether in MDD HPA axis hyperactivity may be due to epigenetic modulation of GR transcript variants. Levels of GRalpha, GRbeta and GR-P transcripts were homogeneous throughout the limbic system, with GRalpha being the most abundant (83%), followed by GR-P (5-6%) while GRbeta was barely detectable (0.02%). Among the alternative first exons, 1B and 1C were the most active, while 1E and 1J showed the lowest expression and transcript 1F expressed intermediate levels of about 1%. In MDD, total GR levels were unaltered, although GRalpha was decreased in the amygdala and cingulate gyrus (p<0.05); transcripts containing exons 1B, 1C and 1F were lower, and 1D and1J were increased in some regions. NGFI-A, a transcription factor of exon 1F was down-regulated in the hippocampus of MDD patients; concomitantly exon 1F expression was reduced. Bisulphite sequencing of the alternative promoters showed low methylation levels in both MDD and control brains. Promoter 1F was uniformly unmethylated, suggesting that reduced 1F transcript levels are not linked to promoter methylation but to the observed dearth of NGFI-A. Previous studies showed high methylation levels in the 1F promoter, associated with childhood abuse. Provided our donors were not abused, our results suggest that the pathomechanism of MDD is similar but nevertheless distinct from that of abuse victims, explaining the clinical similarity of both conditions and that susceptibility to depression may be either predisposed by early trauma or developed independent of such a condition. However, this should be further confirmed in dedicated studies in larger cohorts.Psychoneuroendocrinology 09/2009; 35(4):544-56. · 5.81 Impact Factor