Altered expression of neuroplasticity-related genes in the brain of depressed suicides

Background: Expression of the neuronal membrane glycoprotein M6a (GPM6A), the proteolipid protein (PLP/DM20) family member, is downregulated in the hippocampus of chronically stressed animals. Its neuroplastic function involves a role in neurite formation, filopodium outgrowth and synaptogenesis through an unknown mechanism. Disruptions in neuroplasticity mechanisms have been shown to play a significant part in the etiology of depression. Thus, the current investigation examined whether GPM6A expression is also altered in human depressed brain. Methods: Expression levels and coexpression patterns of GPM6A, GPM6B, and PLP1 (two other members of PLP/DM20 family) as well as of the neuroplasticity-related genes identified to associate with GPM6A were determined using quantitative polymerase chain reaction (qPCR) in postmortem samples from the hippocampus (. n=. 18) and the prefrontal cortex (PFC) (. n=. 25) of depressed suicide victims and compared with control subjects (hippocampus n=. 18; PFC n=. 25). Neuroplasticity-related proteins that form complexes with GPM6A were identified by coimmunoprecipitation technique followed by mass spectrometry. Results: Results indicated transcriptional downregulation of GPM6A and GPM6B in the hippocampus of depressed suicides. The expression level of calcium/calmodulin-dependent protein kinase II alpha (CAMK2A) and coronin1A (CORO1A) was also significantly decreased. Subsequent analysis of coexpression patterns demonstrated coordinated gene expression in the hippocampus and in the PFC indicating that the function of these genes might be coregulated in the human brain. However, in the brain of depressed suicides this coordinated response was disrupted. Conclusions: Disruption of coordinated gene expression as well as abnormalities in GPM6A and GPM6B expression and expression of the components of GPM6A complexes were detected in the brain of depressed suicides.Fil: Fuchsova, Beata. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas ; ArgentinaFil: Alvarez Juliá, Anabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas ; ArgentinaFil: Rizavi, H. S.. University of Illinois; Estados UnidosFil: Frasch, Alberto Carlos C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas ; ArgentinaFil: Pandey, G. N.. University of Illinois; Estados Unido

MicroRNA Expression Is Down-Regulated and Reorganized in Prefrontal Cortex of Depressed Suicide Subjects

<div><h3>Background</h3><p>Recent studies suggest that alterations in expression of genes, including those which regulate neural and structural plasticity, may be crucial in the pathogenesis of depression. MicroRNAs (miRNAs) are newly discovered regulators of gene expression that have recently been implicated in a variety of human diseases, including neuropsychiatric diseases.</p> <h3>Methodology/Principal Findings</h3><p>The present study was undertaken to examine whether the miRNA network is altered in the brain of depressed suicide subjects. Expression of miRNAs was measured in prefrontal cortex (Brodmann Area 9) of antidepressant-free depressed suicide (n = 18) and well-matched non-psychiatric control subjects (n = 17) using multiplex RT-PCR plates. We found that overall miRNA expression was significantly and globally down-regulated in prefrontal cortex of depressed suicide subjects. Using individual tests of statistical significance, 21 miRNAs were significantly decreased at p = 0.05 or better. Many of the down-regulated miRNAs were encoded at nearby chromosomal loci, shared motifs within the 5′-seeds, and shared putative mRNA targets, several of which have been implicated in depression. In addition, a set of 29 miRNAs, whose expression was not pairwise correlated in the normal controls, showed a high degree of co-regulation across individuals in the depressed suicide group.</p> <h3>Conclusions/Significance</h3><p>The findings show widespread changes in miRNA expression that are likely to participate in pathogenesis of major depression and/or suicide. Further studies are needed to identify whether the miRNA changes lead to altered expression of prefrontal cortex mRNAs, either directly (by acting as miRNA targets) or indirectly (e.g., by affecting transcription factors).</p> </div

Asian Capital Market Integration: Theory and Evidence

Financial integration is a multidimensional process through which allocation of financial assets becomes increasingly borderless. This paper assesses the progress achieved thus far in capital market integration in Asia, and compares regional capital market integration with global financial integration. The results of the analysis on which the paper is based indicate that while the pace of regional integration of financial markets in Asia's emerging economies has accelerated in recent years, these markets remain more integrated with global financial markets than with other financial markets in the region. Further, integration of the region's domestic local-currency bond markets with their regional and global counterparts lags the pace of integration of its equity markets. The study also assesses the degree to which volatility in equity- and bond-market returns driven by financial turmoil originating at both the regional and global levels spills over into emerging Asia domestic equity and bond markets. The results of this analysis indicate that such spill-over significantly impacts both domestic equity and bond markets in the region. This finding suggests that ongoing regional capital market integration initiatives should take into account the risk of contagion that regional financial integration presents, and introduce measures for mitigating such risk as a means of ensuring financial stability in the region

Gene Expression and Epigenetic Modifications in Stress Response Genes Associated with Teenage and Adult

Suicide is a preventable public health issue that accounts for over a million deaths worldwide and is associated with the interaction of several biological, environmental, and neurological factors. Repeatedly, a dysregulated hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated to play a fundamental role and associated with psychiatric disorders and suicide, yet the mechanisms underlying this dysregulation are not clear. Decreased expression of the glucocorticoid receptor (GR) which is highly expressed in the hippocampus and prefrontal cortex (PFC) and is susceptible to epigenetic modulation is a strong indicator of HPA-axis hyperactivity. Additionally, epigenetic mechanisms have been shown to mediate environment x gene interaction through susceptible genes resulting in long-term changes to the genome. One of the most studied epigenetic mark, DNA methylation (DNAm) has been demonstrated to play a major role in various diseases including suicide. The main goal of this thesis was to test the hypothesis that HPA-axis coupled genes are dysregulated in specific areas of the limbic system and that epigenetic reprogramming, in the form of DNAm, maybe a key underlying factor mediating impaired GR signaling. Since there are distinct neurodevelopmental changes occurring during adolescence that may change the endophenotypes of suicide, teenage suicide-completers were studied separately from adult suicide-completers. In teenage suicide-completers, a focused approach was used to identify HPA-axis coupled genes that are differentially expressed and determine significant methylation changes at specific loci of candidate genes. To investigate steady-state DNAm levels, we analyzed DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TETs), and growth arrest- and DNA-damage-inducible proteins (GADD45) in both PFC and hippocampus. In adult suicide-completers, a hypothesis-free, genome-wide approach was taken to determine DNAm changes specific to neurons in the PFC. Initial bioinformatics reveals novel molecular pathways and networks where epigenetic regulation may be playing a key underlying factor. Together, these findings enhance our understanding of the complex transcriptional regulation of GR gene and also identify key regulators involved in HPA-axis dysregulation. Integrating DNAm and gene expression analysis provides valuable insight into molecular changes and help develop our current knowledge of how epigenetics contributes to alterations in molecular pathways involved in the pathophysiology of suicide

Expression of p21-activated kinases 1 and 3 is altered in the brain of subjects with depression

The p21-activated kinases (PAKs) of group I are the main effectors for the small Rho GTPases, critically involved in neurodevelopment, plasticity and maturation of the nervous system. Moreover, the neuronal complexity controlled by PAK1/PAK3 signaling determines the postnatal brain size and synaptic properties. Stress induces alterations at the level of structural and functional synaptic plasticity accompanied by reductions in size and activity of the hippocampus and the prefrontal cortex (PFC). These abnormalities are likely to contribute to the pathology of depression and, in part, reflect impaired cytoskeleton remodeling pointing to the role of Rho GTPase signaling. Thus, the present study assessed the expression of the group I PAKs and their activators in the brain of depressed subjects. Using quantitative polymerase chain reaction (qPCR), mRNA levels and coexpression of the group I PAKs: PAK1, PAK2, and PAK3 as well as of their activators: RAC1, CDC42 and ARHGEF7 were examined in postmortem samples from the PFC (n = 25) and the hippocampus (n = 23) of subjects with depression and compared to control subjects (PFC n = 24; hippocampus n = 21). Results demonstrated that mRNA levels of PAK1 and PAK3, are significantly reduced in the brain of depressed subjects, with PAK1 being reduced in the PFC and PAK3 in the hippocampus. No differences were observed for the ubiquitously expressed PAK2. Following analysis of gene coexpression demonstrated disruption of coordinated gene expression in the brain of subjects with depression. Abnormalities in mRNA expression of PAK1 and PAK3 as well as their altered coexpression patterns were detected in the brain of subjects with depression.Fil: Fuchsova, Beata. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas ; ArgentinaFil: Alvarez Juliá, Anabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas ; ArgentinaFil: Rizavi, Hooriyah S.. University of Illinois; Estados UnidosFil: Frasch, Alberto Carlos C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas ; ArgentinaFil: Pandey, Ghanshyam N.. University of Illinois; Estados Unido

Altered Wnt signalling in the teenage suicide brain: focus on glycogen synthase kinase-3b and b-catenin

Glycogen synthase kinase (GSK)-3β and β-catenin are important components of the Wnt signalling pathway, which is involved in numerous physiological functions such as cognition, brain development and cell survival. Their abnormalities have been implicated in mood disorders and schizophrenia. Teenage suicide is a major public health concern; however, very little is known about its neurobiology. In order to examine if abnormalities of GSK-3β and β-catenin are associated with teenage suicide, we determined the gene and protein expression of GSK-3β and β-catenin in the prefrontal cortex (PFC) and hippocampus obtained from 24 teenage suicide victims and 24 normal control subjects. Protein expression was determined using Western blot with specific antibodies and gene expression (mRNA levels) was determined using the real-time polymerase chain reaction method. No significant change was observed in the GSK-3β protein levels either in the PFC or hippocampus of suicide victims compared to controls. However, protein levels of pGSK-3β-ser9 were significantly decreased in the PFC and hippocampus of suicide victims compared to normal controls. We also found that GSK-3β mRNA levels were significantly decreased in the PFC but not in the hippocampus of teenage suicide victims compared to controls. Mean protein and mRNA levels of β-catenin were significantly decreased in both the PFC and hippocampus of teenage suicide group compared to controls. The observation that there is a decrease in β-catenin and pGSK-3β-ser9 in the PFC and hippocampus of teenage suicide victims does indicate a disturbance in the Wnt signalling pathway in teenage suicide

Characteristics of subjects in the depressed suicide and normal control groups.

<p>Characteristics of subjects in the depressed suicide and normal control groups.</p

Plot of Mean vs standard deviation (SD) for normal control and depressed suicide groups.

<p>miRNA expression in the depressed suicide group is significantly <i>less</i> variable than in the control group.</p