Homer1a protein expression in schizophrenia, bipolar disorder, and major depression.

In recent years, there was growing interest in postsynaptic density proteins in the central nervous system. Of the most important candidates of this specialized region are proteins belonging to the Homer protein family. This family of scaffolding proteins is suspected to participate in the pathogenesis of a variety of diseases. The present study aims to compare Homer1a expression in the hippocampus and cingulate gyrus of patients with major psychiatric disorders including schizophrenia, bipolar disorder and major depression. Immunohistochemistry was used to analyze changes of Homer1a protein expression in the hippocampal formation and the cingulate gyrus from the respective disease groups. Glial cells of the cingulate gyrus gray matter showed decreased Homer1a levels in bipolar disorder when compared to controls. The same results were seen when comparing cingulate gyrus gray matter glial cells in bipolar disorder with major depression. Stratum oriens glial cells of the hippocampus showed decreased Homer1a levels in bipolar disorder when compared to controls and major depression. Stratum lacunosum glial cells showed decreased Homer1a levels in bipolar disorder when compared to major depression. In stratum oriens interneurons Homer1a levels were increased in all disease groups when compared to controls. Stratum lucidum axons showed decreased Homer1a levels in bipolar disorder when compared to controls. Our data demonstrate altered Homer1a levels in specific brain regions and cell types of patients suffering from schizophrenia, bipolar disorder and major depression. These findings support the role of Homer proteins as interesting candidates in neuropsychiatric pathophysiology and treatment.

Increased expression of retinoic acid-induced gene 1 in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression.

BACKGROUND: Retinoids regulate gene expression in different cells and tissues at the transcriptional level. Retinoic acid transcriptionally regulates downstream regulatory molecules, including enzymes, transcription factors, cytokines, and cytokine receptors. Animal models indicate an involvement of retinoid signaling pathways in the regulation of synaptic plasticity and learning, especially in the hippocampus. Retinoic acid-inducible or induced gene 1 (RAI-1) is induced during neuronal differentiation, and was associated with the severity of the phenotype and response to medication in schizophrenic patients. METHODS: In the present study, we used immunohistochemistry to investigate the expression of RAI-1 in 60 brains from the Stanley Neuropathology Consortium (15 cases each from controls and from patients with schizophrenia, bipolar disorder, and major depression). Rating scores for density and intensity were determined in the dorsolateral prefrontal cortex. RESULTS: All four groups showed high interindividual variation. RAI-1-positive cells were identified as neurons and astrocytes. Significantly increased intensities in cortical neurons were noted in all three major psychiatric groups compared with controls. The density of RAI-1-positive neurons was increased (P=0.06) in schizophrenia and bipolar disorder. In bipolar disorder, RAI-1-positive astrocytes in gray matter showed a significantly increased intensity and compound value. Thus, a significant increase in the parameters measured was found in schizophrenia, bipolar disorder, and major depression. CONCLUSION: Our study shows a significant increase in expression of RAI-1 in the brains from patients with schizophrenia, bipolar disorder, or major depression. The increased expression might reflect altered signaling pathways, like that for retinoic acid. The underlying mechanisms leading to the increased expression and its functional consequences are so far unknown, and remain to be investigated in future studies.

Effects of typical and atypical antipsychotic drugs on gene expression profiles in the liver of schizophrenia subjects.

BACKGROUND: Although much progress has been made on antipsychotic drug development, precise mechanisms behind the action of typical and atypical antipsychotics are poorly understood. METHODS: We performed genome-wide expression profiling to study effects of typical antipsychotics and atypical antipsychotics in the postmortem liver of schizophrenia patients using microarrays (Affymetrix U133 plus2.0). We classified the subjects into typical antipsychotics (n = 24) or atypical antipsychotics (n = 26) based on their medication history, and compared gene expression profiles with unaffected controls (n = 34). We further analyzed individual antipsychotic effects on gene expression by sub-classifying the subjects into four major antipsychotic groups including haloperidol, phenothiazines, olanzapine and risperidone. RESULTS: Typical antipsychotics affected genes associated with nuclear protein, stress responses and phosphorylation, whereas atypical antipsychotics affected genes associated with golgi/endoplasmic reticulum and cytoplasm transport. Comparison between typical antipsychotics and atypical antipsychotics further identified genes associated with lipid metabolism and mitochondrial function. Analyses on individual antipsychotics revealed a set of genes (151 transcripts, FDR adjusted p < 0.05) that are differentially regulated by four antipsychotics, particularly by phenothiazines, in the liver of schizophrenia patients. CONCLUSION: Typical antipsychotics and atypical antipsychotics affect different genes and biological function in the liver. Typical antipsychotic phenothiazines exert robust effects on gene expression in the liver that may lead to liver toxicity. The genes found in the current study may benefit antipsychotic drug development with better therapeutic and side effect profiles.

The high-affinity niacin receptor HM74A is decreased in the anterior cingulate cortex of individuals with schizophrenia.

The pathway for de novo synthesis of the suite of niacin congeners, the kynurenine pathway, has been shown to be upregulated in prior studies of postmortem brain tissue from individuals with schizophrenia. The cause of the upregulation is unknown, but one factor may be a defect in feedback regulation via receptors responsive to niacin. A high-affinity and low-affinity receptor for niacin have been identified, HM74A and HM74, respectively. We used RT-QPCR and Western blots to quantify expression of HM74A and HM74 receptors in brain tissue obtained postmortem from patients with schizophrenia (N=12) or bipolar disorder (N=14) and from normal controls (N=14). Although the protein for the HM74 receptor was unchanged, the protein for HM74A was significantly decreased in the schizophrenia group, both when normalized to GAPDH protein or to HM74 as an internal control for degradation and gel-loading error (0.56-fold+/-0.36, p=0.016 and 0.58-fold+/-0.19 the mean control value, p=0.001, respectively). In contrast, the transcript for HM74A was significantly increased, revealing a striking dysregulation between gene transcription and final protein product. No significant differences in HM74A were found for the bipolar group relative to controls. These results are consistent with the blunted niacin flush response reported for individuals with schizophrenia and may be relevant to different rates of comorbid disease.

Expression of cellular prion protein (PrP(c)) in schizophrenia, bipolar disorder, and depression.

Cellular prion protein (PrP(c)) is a copper-binding, membrane-attached GPI-anchored glycoprotein characterized by a high degree of amino acid sequence conservation among mammals. PrP(c) expression has been demonstrated in neurons, microglia, lymphocytes, and keratinocytes. Recently, the concept that PrP(c) may be involved in the defense against oxidative stress was advanced. In the present study, we used immunohistochemistry for PrP(c) to investigate 60 brains from the Stanley Neuropathology Consortium (15 controls, 15 patients with schizophrenia, 15 with bipolar disorder, and 15 with major depression). Rating scores as well as the numerical density of PrP(c)-positive and -negative neurons and glial cells were determined in the cingulate gyrus. All four groups showed a very high interindividual variation. PrP(c)-positive glial cells were significantly reduced in the white matter of patients with schizophrenia, bipolar disorder, and major depression. A similar result was obtained for the white matter in bipolar patients using rating scales. From the confounding variables, use of medication (i.e. antipsychotics, antidepressants, and mood stabilizers) had a significant effect on the expression of PrP(c) by neurons and glial cells. PrP(c)-immunoreactivities were significantly reduced for white matter glial cells in all examined groups. However, the results are not indicative for the occurrence of oxidative stress in the brains of schizophrenic and bipolar patients. Since the effect of antipsychotic and antidepressant medication as well as of mood stabilizers on the expression of PrP(c) was significant, it needs further clarification in experimental models.

Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder.

Upregulation of the kynurenine pathway has been associated with several etiologies of psychosis, an indication that increased levels of pathway intermediates might be involved in eliciting some psychotic features. In schizophrenia, tryptophan 2,3-dioxygenase (TDO2) was previously identified in postmortem frontal cortex as the enzyme likely responsible for the reported increase in pathway activity in the brain. For this follow-up study of postmortem anterior cingulate gyrus, we have found evidence of increased TDO2 activity in schizophrenia at three different levels of regulation: mRNA, protein, and metabolic product. The results were unaffected by neuroleptic status or smoking history. To make the distinction between mental disorders with psychosis and those without, this study included patients with bipolar disorder and major depression. Compared to the control group, the HPLC, RT-PCR, and immunohistochemistry results show significant elevation of (1) kynurenine in schizophrenia (1.9-fold, P = 0.02), and in bipolar disorder (1.8-fold, P = 0.04), primarily in the bipolar subgroup with psychosis (2.1-fold, P = 0.03); (2) TDO2 mRNA in schizophrenia (1.7-fold; P = 0.049); and (3) the immunohistochemistry values for the density of TDO2-positive white matter glial cells in schizophrenia (P = 0.01) and in major depression (P = 0.03) as well as the density and intensity of glial cells (in both gray and white matter) stained for TDO2 in bipolar disorder (P = 0.02). Unlike the results for schizophrenia and bipolar disorder, the increase in TDO2 protein in the major depression group was not associated with an increase in kynurenine concentration.