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Josué Pérez-Santiago,
Rebeca Diez-Alarcia,
Luis F Callado,
Jin X Zhang,
Gursharan Chana,
Cory H White,
Stephen J Glatt,
Ming T Tsuang, Ian P Everall,
J Javier Meana,
Christopher H Woelk
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ABSTRACT: Small cohort sizes and modest levels of gene expression changes in brain tissue have plagued the statistical approaches employed in microarray studies investigating the mechanism of schizophrenia. To combat these problems a combined analysis of six prior microarray studies was performed to facilitate the robust statistical analysis of gene expression data from the dorsolateral prefrontal cortex of 107 patients with schizophrenia and 118 healthy subjects. Multivariate permutation tests identified 144 genes that were differentially expressed between schizophrenia and control groups. Seventy of these genes were identified as differentially expressed in at least one component microarray study but none of these individual studies had the power to identify the remaining 74 genes, demonstrating the utility of a combined approach. Gene ontology terms and biological pathways that were significantly enriched for differentially expressed genes were related to neuronal cell-cell signaling, mesenchymal induction, and mitogen-activated protein kinase signaling, which have all previously been associated with the etiopathogenesis of schizophrenia. The differential expression of BAG3, C4B, EGR1, MT1X, NEUROD6, SST and S100A8 was confirmed by real-time quantitative PCR in an independent cohort using postmortem human prefrontal cortex samples. Comparison of gene expression between schizophrenic subjects with and without detectable levels of antipsychotics in their blood suggests that the modulation of MT1X and S100A8 may be the result of drug exposure. In conclusion, this combined analysis has resulted in a statistically robust identification of genes whose dysregulation may contribute to the mechanism of schizophrenia.
Journal of psychiatric research 09/2012; 46(11):1464-74. · 3.72 Impact Factor
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ABSTRACT: In recent years, human immunodeficiency virus (HIV)-infected patients under highly active anti-retroviral therapy (HAART)
regimens have shown a markedly improved general clinical status; however, the prevalence of mild cognitive disorders has increased.
We propose that increased longevity with HIV-mediated chronic inflammation combined with the secondary effects of HAART may
increase the risk of early brain aging as shown by intraneuronal accumulation of abnormal protein aggregates like amyloid
β (Aβ), which might participate in worsening the neurodegenerative process and cognitive impairment in older patients with
HIV. For this purpose, levels and distribution of Aβ immunoreactivity were analyzed in the frontal cortex of 43 patients with
HIV (ages 38–60) and HIV− age-matched controls. Subcellular localization of the Aβ-immunoreactive material was analyzed by
double labeling and confocal microscopy and by immunono-electron microscopy (EM). Compared to HIV− cases, in HIV+ cases, there
was abundant intracellular Aβ immunostaining in pyramidal neurons and along axonal tracts. Cases with HIV encephalitis (HIVE)
had higher levels of intraneuronal Aβ immunoreactivity compared to HIV+ cases with no HIVE. Moreover, levels of intracellular
Aβ correlated with age in the group with HIVE. Double-labeling analysis showed that the Aβ-immunoreactive granules in the
neurons co-localized with lysosomal markers such as cathepsin-D and LC3. Ultrastructural analysis by immuno-EM has confirmed
that in these cases, intracellular Aβ was often found in structures displaying morphology similar to autophagosomes. These
findings suggest that long-term survival with HIV might interfere with clearance of proteins such as Aβ and worsen neuronal
damage and cognitive impairment in this population.
Journal of Neuroimmune Pharmacology 04/2012; 4(2):190-199. · 4.57 Impact Factor
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ABSTRACT: Microglial activation and alterations in neuron number have been reported in autism. However, it is unknown whether microglial activation in the disorder includes a neuron-directed microglial response that might reflect neuronal dysfunction, or instead indicates a non-directed, pro-activation brain environment. To address this question, we examined microglial and neuronal organization in the dorsolateral prefrontal cortex, a region of pronounced early brain overgrowth in autism, via spatial pattern analysis of 13 male postmortem autism subjects and 9 controls. We report that microglia are more frequently present near neurons in the autism cases at a distance interval of 25 μm, as well as 75 and 100 μm. Many interactions are observed between near-distance microglia and neurons that appear to involve encirclement of the neurons by microglial processes. Analysis of a young subject subgroup preliminarily suggests that this alteration may be present from an early age in autism. We additionally observed that neuron-neuron clustering, although normal in cases with autism as a whole, increases with advancing age in autism, suggesting a gradual loss of normal neuronal organization in the disorder. Microglia-microglia organization is normal in autism at all ages, indicating that aberrantly close microglia-neuron association in the disorder is not a result of altered microglial distribution. Our findings confirm that at least some microglial activation in the dorsolateral prefrontal cortex in autism is associated with a neuron-specific reaction, and suggest that neuronal organization may degrade later in life in the disorder.
Brain research 03/2012; 1456:72-81. · 2.46 Impact Factor
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ABSTRACT: FK506 binding protein (FKBP)-51 and FKBP52 act as molecular chaperones to control glucocorticoid receptor (GR) sensitivity. Dysregulation of proteins involved in GR-mediated signaling can lead to maladaptive stress response and aging-related cognitive decline. As HIV infection is related to chronic stress, we hypothesized that altered cortical expression of these proteins was associated with HIV-associated neurocognitive disorders (HAND). We used quantitative immunohistochemistry to assess expression levels of these proteins in the mid-frontal gyrus of 55 HIV-infected subjects free of cerebral opportunistic diseases compared to 20 age-matched non-HIV controls. The immunoreactivity normalized to the neuroanatomic area measured (IRn) for FKBP51 was increased in HIV subjects both in the cortex and subcortical white matter (p < 0.0001, U test), while no significant alterations were observed for GR or FKBP52. Notably, the cortical FKBP51 IRn was higher in HAND subjects than in cognitively normal HIV subjects (p = 0.02, U test). There was also a trend for increasing cortical FKBP51 IRn with the increasing severity of HAND (p = 0.08, Kruskal-Wallis test). No significant changes in FKBP51 IRn were found with respect to hepatitis C virus infection, lifetime methamphetamine use, or antiretroviral treatment in HIV subjects. In conclusion, the increased cortical expression of FKBP51 (an inhibitor for GR activity) might represent negative feedback in an attempt to reduce GR sensitivity in the setting of chronic stress-induced elevation of GR-mediated signaling inherent in HIV infection. The further increased FKBP51 expression might lead to maladaptive stress response and HAND.
Journal of NeuroVirology 01/2012; 18(4):313-22. · 2.31 Impact Factor
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ABSTRACT: Little is known about the medical status of individuals entering treatment for co-occurring substance abuse and other mental disorders (COD). We analyzed the medical histories of 169 adults entering outpatient treatment for CODs, estimating lifetime prevalence of chronic illness and current smoking, comparing these rates to the general population, and examining psychiatric and substance-related correlates of chronic illness. Results revealed significantly higher prevalence of hypertension, asthma, arthritis, and smoking compared to the general US population, and showed an association between chronic illness and psychiatric symptom distress and substance use severity. Findings support integration of chronic illness management into COD treatment.
American Journal on Addictions 01/2012; 21(1):1-4. · 1.74 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) infection is a serious problem among those co-infected with human immunodeficiency virus; however, its impact in the central nervous system (CNS) remains unclear. This study aimed to investigate the mechanisms underlying HCV core protein-mediated neurodegeneration. Analysis of human HCV seropositive cases demonstrated widespread damage to neuronal dendritic processes and sustained activation of extracellular signal-related kinase (ERK); analogous pathologies were observed in wild type injected with HCV core protein into the hippocampus. In vitro analysis in neuronal cells exposed to HCV core demonstrated retraction of the neuronal processes in an ERK/Signal Transducer and Activator of Transcription 3 (STAT3)-dependent manner dependent on toll-like receptor 2 (TLR2) signaling activation. These results indicate that HCV core protein neurotoxicity may be mediated by the sustained activation of ERK/STAT3 via TLR2-IRAK1 signaling pathway. These pathways provide novel targets for development of neuroprotective treatments for HCV involvement of the CNS.
Journal of NeuroVirology 06/2011; 17(4):327-40. · 2.31 Impact Factor
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ABSTRACT: Methamphetamine-associated psychosis (MAP) has been considered a pharmacological or environmental pathogen model of schizophrenia
(SCZ) due in part to similarities in clinical presentation (i.e. paranoia, hallucinations, disorganized speech, and negative
symptoms), response to treatment (e.g. neuroleptics), and pathologic mechanisms (e.g. central dopaminergic neurotransmission)
of both conditions. In this chapter, we will provide an introduction to the typical clinical features and course of MAP as
well as a review and discussion of the current putative genetic biomarkers for MAP. We will conclude with a discussion of
the future directions and application of the MAP model with specific focus on how it may serve to elucidate further the complex
neuromechanisms and discovery of viable biomarkers of SCZ.
KeywordsMethamphetamine-Model of psychosis-Genetic-Biomarkers
06/2011: pages 327-343;
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ABSTRACT: Macrophages are one of HIV-1's principal targets and chiefly responsible for translocating HIV into the central nervous system (CNS). Previous research suggested an increase in macrophages being infected by HIV in the presence of methamphetamine (METH) or increased extracellular dopamine (DA). Experimental studies indicate that this is mediated by DA receptors, including DA receptor D3 (DRD3), which is expressed in macrophages. A single nucleotide polymorphism (SNP) of the DRD3 gene (rs6280TC) modulates its dopamine binding affinity, resulting in the possibility that inheriting a variant of this SNP increases macrophage susceptibility to HIV infection in the presence of METH and DA, particularly in the CNS where METH is sequestered, leading to cognitive impairment (CI). Thus, we conducted a retrospective clinical investigation to evaluate whether rs6280TC is associated with CI among HIV-positive METH users. We stratified 310 males by HIV serostatus (HIV-positive, -negative) and METH dependence (METH-positive, -negative) and then by rs6280TC genotype (CC, CT, and TT). Genotypic groups within each of four HIV/METH groups were compared for rates of CI. We hypothesized that only HIV-positive/METH-positive carriers of the C allele, which increases the DRD3's binding to DA, would be more likely to develop CI. Cochran-Armitage test for trends in proportions yielded significant (p < 0.05) association between three genotypes and impairment rates in the hypothesized order, but only among HIV-positive/METH-positive subjects. The results also confirmed that C allele carriers (CC and CT, 53.3%) in this group had higher impairment rates (p = 0.05) than TT carriers (33.3%). These findings support the theory that rs6280TC influences the frequency of CI in HIV-positive/METH-positive males.
Journal of NeuroVirology 06/2011; 17(3):239-47. · 2.31 Impact Factor
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ABSTRACT: The role of the cerebellum in coordinating mental activity is supported by its connections with cerebral regions involved in cognitive/affective functioning, with decreased activities on functional neuroimaging observed in the cerebellum of schizophrenia patients performing mental tasks. Brain-derived neurotrophic factor (BDNF)-induced activation of tyrosine kinase B (TrkB) is essential to synaptic plasticity. We hypothesized that alterations in BDNF and TrkB expression in the cerebellum were associated with schizophrenia and affective disorders.
We employed immunohistochemistry and immunoblotting to quantify protein expression of BDNF and TrkB in the cerebellum of patients with schizophrenia, bipolar disorder, and major depression compared to controls (n=15 each).
While TrkB immunoreactivity in each of the molecular and granule-cell layers was reduced in all 3 disease groups (12-34%) compared to the control (P=0.018 and 0.038, respectively, ANOVA), only the reduction in bipolar disorder remained statistically significant upon Tukey-Kramer post hoc analyses (P=0.019 and 0.021, respectively). Apparent decreases in BDNF immunoreactivity in all 3 disease groups (12-30%) compared to the control were not statistically significant. TrkB immunoreactivity was not significantly associated with any of the demographic, clinical, and postmortem variables. Immunoblotting displayed an 85-kDa TrkB-immunoreactive band, consistent with a truncated isoform, in all 60 cases.
On immunoblotting, apparent decreases in 85-kDa-TrkB levels in all 3 disease groups compared to the control were not statistically significant.
Our finding of reduced TrkB expression in bipolar disorder suggests that dysregulation of TrkB-mediated neurotrophin signaling in the cerebellum may play a role in the pathophysiology of this disease.
Journal of affective disorders 05/2011; 133(3):646-54. · 3.76 Impact Factor
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ABSTRACT: Recent treatments with highly active antiretroviral therapy (HAART) regimens have been shown to improve general clinical status in patients with human immunodeficiency virus (HIV) infection; however, the prevalence of cognitive alterations and neurodegeneration has remained the same or has increased. These deficits are more pronounced in the subset of HIV patients with the inflammatory condition known as HIV encephalitis (HIVE). Activation of signaling pathways such as GSK3β and CDK5 has been implicated in the mechanisms of HIV neurotoxicity; however, the downstream mediators of these effects are unclear. The present study investigated the involvement of CDK5 and tau phosphorylation in the mechanisms of neurodegeneration in HIVE. In the frontal cortex of patients with HIVE, increased levels of CDK5 and p35 expression were associated with abnormal tau phosphorylation. Similarly, transgenic mice engineered to express the HIV protein gp120 exhibited increased brain levels of CDK5 and p35, alterations in tau phosphorylation, and dendritic degeneration. In contrast, genetic knockdown of CDK5 or treatment with the CDK5 inhibitor roscovitine improved behavioral performance in the water maze test and reduced neurodegeneration, abnormal tau phosphorylation, and astrogliosis in gp120 transgenic mice. These findings indicate that abnormal CDK5 activation contributes to the neurodegenerative process in HIVE via abnormal tau phosphorylation; thus, reducing CDK5 might ameliorate the cognitive impairments associated with HIVE.
American Journal Of Pathology 04/2011; 178(4):1646-61. · 4.89 Impact Factor
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ABSTRACT: Homelessness has been associated with neuropsychological (NP) impairment, but few studies have adequately controlled for factors known to affect NP performance. We performed brief NP testing examining learning, recall, processing speed, executive functioning, and verbal fluency in 50 ever- and 22 never-homeless persons entering outpatient psychiatric treatment. Groups were matched a priori on key demographic, substance use, psychiatric, and premorbid intelligence quotient characteristics. Rates of NP impairment were high among both groups (46%-54%). There were no significant differences in global NP impairment. There were trends toward better levels of processing speed and executive functioning among never-homeless relative to ever-homeless. Among the ever-homeless group, NP test performance was unrelated to number of homelessness episodes (median 3). Findings confirm high prevalence of NP impairment among homeless individuals but provide little evidence for broad NP differences between ever- and never-homeless persons matched for coexisting conditions that have confounded interpretation of previous results in the literature.
The Journal of nervous and mental disease 11/2010; 198(11):790-4. · 1.77 Impact Factor
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ABSTRACT: Several brain- and blood-based gene expression studies in patients with psychotic disorders (e.g., schizophrenia) have identified genes in the ubiquitin proteasome system (UPS) pathway as putative biomarkers. However, to date an examination of the UPS pathway in the broader context of symptom severity in psychosis has not been conducted. The purpose of this study was to investigate the correlation between clinical scores on the Scales for the Assessment of Positive and Negative Symptoms (SAPS-SANS) and expression of 43 highly annotated genes within the UPS pathway in blood from patients with psychosis. A sample of 19 psychotic patients diagnosed with schizophrenia (n = 13) or bipolar disorder (n = 6) were recruited. Pearson's partial correlations, adjusting for gender, ethnicity, age, education, medication, smoking, and past 6-month substance use, were performed between each of the selected UPS genes and both scales. Significant Bonferroni-adjusted positive associations were observed between SAPS scores and two ubiquitin conjugation genes (i.e., UBE2K, SIAH2), while a negative association was observed with one deubiquitination gene (i.e., USP2). No gene expression levels were significantly associated with scores on the SANS after correction for multiple testing. Our findings suggest that dysregulation of the UPS, specifically ubiquitin conjugation and deubiquitination, may point to a possible underlying biological mechanism for severity of positive but not negative symptoms.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2010; 153B(7):1336-41. · 3.70 Impact Factor
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ABSTRACT: Major depressive disorder (MDD) is a significant cause of morbidity in people living with the human immunodeficiency virus (HIV). FKBP5 is a candidate gene with single-nucleotide polymorphisms (SNPs) rs1360780 and rs3800373 associated with MDD. This gene product and its relative, FKBP4, physically associate with the glucocorticoid receptor whose function is implicated in MDD pathophysiology. Because these genes are expressed in blood and brain and elevated in HIV infection, we explored the relationship between gene expression, genotype, and MDD symptoms. Longitudinally followed subjects (N = 57) as part of the CNS HIV AntiRetroviral Effects Research study, with diagnosed MDD and who donated blood for genotyping and gene expression analysis, were assessed. Subjects donated blood on adjacent visits with and without meeting criteria for MDD episode. Changes in clinical parameters were compared changes in gene expression. Change in FKBP5 expression correlated with change in Beck Depression Inventory (BDI) for MDD → euthymic comparison in GG genotype of rs3800373 (P = .013) and TT carriers of rs1360780 (P = .02). In euthymic → MDD comparison, GG homozygous, FKBP5 expression correlated with more severe change in BDI. Change in FKBP4 expression did not correlate with changes in clinical or depression measurements. Higher FKBP5 expression correlated with greater symptom change for GG carriers of rs3800373.
Journal of NeuroVirology 10/2010; 16(5):399-404. · 2.31 Impact Factor
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ABSTRACT: In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been reported. However, it is unknown whether microglial somal volume or density are altered in the cortex and whether any alteration is associated with age or other potential covariates.
Microglia in sections from the dorsolateral prefrontal cortex of nonmacrencephalic male cases with autism (n = 13) and control cases (n = 9) were visualized via ionized calcium binding adapter molecule 1 immunohistochemistry. In addition to a neuropathological assessment, microglial cell density was stereologically estimated via optical fractionator and average somal volume was quantified via isotropic nucleator.
Microglia appeared markedly activated in 5 of 13 cases with autism, including 2 of 3 under age 6, and marginally activated in an additional 4 of 13 cases. Morphological alterations included somal enlargement, process retraction and thickening, and extension of filopodia from processes. Average microglial somal volume was significantly increased in white matter (p = .013), with a trend in gray matter (p = .098). Microglial cell density was increased in gray matter (p = .002). Seizure history did not influence any activation measure.
The activation profile described represents a neuropathological alteration in a sizeable fraction of cases with autism. Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients. Alternatively, activation may represent a response of the innate neuroimmune system to synaptic, neuronal, or neuronal network disturbances, or reflect genetic and/or environmental abnormalities impacting multiple cellular populations.
Biological psychiatry 08/2010; 68(4):368-76. · 8.93 Impact Factor
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ABSTRACT: Research into the biological processes that increase susceptibility to methamphetamine dependence has been conducted primarily in Asian populations. Using a case-control design this study's purpose was to explore, among a population of methamphetamine-dependent Caucasians, six putative single nucleotide polymorphisms previously found to be associated with methamphetamine dependence in Asian populations. A total of 193 non-psychotic males (117 methamphetamine-dependent and 76 controls) were genotyped for variants located in six genes (AKT1, ARRB2, BDNF, COMT, GSTP1, OPRM1). Genotypic and allelic frequencies, odds ratios, and 95% confidence intervals were calculated. None of the putative gene associations was significantly replicated in our sample of Caucasian men. Effect size comparisons suggest a trend toward allelic divergence for arrestin beta 2 (ARRB2) and glutathione S-transferase P1 (GSTP1) and allelic convergence for brain-derived neurotrophic factor (BDNF). Results provide preliminary support for further exploration and validation of candidate single nucleotide polymorphisms (SNPs) for methamphetamine (METH) dependence reported among Asian populations across other ethnic/ancestral groups.
Psychiatry Research 07/2010; 178(2):295-8. · 2.52 Impact Factor
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ABSTRACT: Glycogen synthase kinase-3β (GSK3β) role in human immunodeficiency virus (HIV)-associated neurodegeneration has been evidenced by previous investigations. In this study, we investigated the specificity of two GSK3β-specific inhibitors, AR-A014418 (A) and B6B30 (B) to prevent direct neurotoxicity in primary human neurons exposed to HIV (BaL). Neurons were exposed to HIV (500 pg/ml) for 12-h and 6-day periods in the presence and absence of A (1 μM, 100 nM, 10 nM) and B (50 nM, 5 nM, 500 pM) to investigate acute and ongoing mechanisms of HIV neurotoxicity. Using an lactate dehydrogenase (LDH) assay to assess cytotoxicity, we observed a significant neurotoxic effect of HIV from control values (P < .01) that was not restored via coexposures of all concentrations of A and B. Additionally, no change in LDH levels were observed after 6 days. However, activity of the acute proapoptotic markers caspases 3 and 7 using a luminescence assay were measured and found to be increased by exposure to HIV (BaL) compared to controls (P = .022). This effect was ameliorated via coexposure to all concentrations of A and 50 nM B after 12 h (P < .01) and to all concentrations of A and B after 6 days (P < .01). Overall, the results from this study provide further evidence for the ability of GSK3β inhibition to be neuroprotective against HIV-associated neurotoxicity by reducing HIV associated procaspase induction. These data support a role for GSK3β as a potential therapeutic target and may have important clinical implications for treatment of HIV-associated neurocognitive disorder.
02/2010; 15(5-6):434-438.
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ABSTRACT: In the rodent forebrain GABAergic neurons are generated from progenitor cells that express the transcription factors Dlx1 and Dlx2. The Rap-1 guanine nucleotide exchange factor, MR-GEF, is turned on by many of these developing GABAergic neurons. Expression of both Dlx1/2 and MR-GEF is retained in both adult mouse and human forebrain where, in human, decreased Dlx1 expression has been associated with psychosis. Using in situ hybridization studies we show that MR-GEF expression is significantly down-regulated in the forebrain of Dlx1/2 double mutant mice suggesting that MR-GEF and Dlx1/2 form part of a common signalling pathway during GABAergic neuronal development. We therefore compared MR-GEF expression by in situ hybridization in individuals with major psychiatric disorders (schizophrenia, bipolar disorder, major depression) and control individuals. We observed a significant positive correlation between layers II and IV of the dorso-lateral prefrontal cortex (DLPFC) in the percentage of MR-GEF expressing neurons in individuals with bipolar disorder, but not in individuals with schizophrenia, major depressive disorder or in controls. Since MR-GEF encodes a Rap1 GEF able to activate G-protein signalling, we suggest that changes in MR-GEF expression could potentially influence neurotransmission.
PLoS ONE 01/2010; 5(4):e10392. · 4.09 Impact Factor
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ABSTRACT: HIV infection disturbs the central nervous system (CNS) through inflammation and glial activation. Evidence suggests roles for microRNA (miRNA) in host defense and neuronal homeostasis, though little is known about miRNAs' role in HIV CNS infection. MiRNAs are non-coding RNAs that regulate gene translation through post-transcriptional mechanisms. Messenger-RNA profiling alone is insufficient to elucidate the dynamic dance of molecular expression of the genome. We sought to clarify RNA alterations in the frontal cortex (FC) of HIV-infected individuals and those concurrently infected and diagnosed with major depressive disorder (MDD). This report is the first published study of large-scale miRNA profiling from human HIV-infected FC. The goals of this study were to: 1. Identify changes in miRNA expression that occurred in the frontal cortex (FC) of HIV individuals, 2. Determine whether miRNA expression profiles of the FC could differentiate HIV from HIV/MDD, and 3. Adapt a method to meaningfully integrate gene expression data and miRNA expression data in clinical samples. We isolated RNA from the FC (n = 3) of three separate groups (uninfected controls, HIV, and HIV/MDD) and then pooled the RNA within each group for use in large-scale miRNA profiling. RNA from HIV and HIV/MDD patients (n = 4 per group) were also used for non-pooled mRNA analysis on Affymetrix U133 Plus 2.0 arrays. We then utilized a method for integrating the two datasets in a Target Bias Analysis. We found miRNAs of three types: A) Those with many dysregulated mRNA targets of less stringent statistical significance, B) Fewer dysregulated target-genes of highly stringent statistical significance, and C) unclear bias. In HIV/MDD, more miRNAs were downregulated than in HIV alone. Specific miRNA families at targeted chromosomal loci were dysregulated. The dysregulated miRNAs clustered on Chromosomes 14, 17, 19, and X. A small subset of dysregulated genes had many 3' untranslated region (3'UTR) target-sites for dysregulated miRNAs. We provide evidence that certain miRNAs serve as key elements in gene regulatory networks in HIV-infected FC and may be implicated in neurobehavioral disorder. Finally, our data indicates that some genes may serve as hubs of miRNA activity.
PLoS ONE 01/2010; 5(4):e10337. · 4.09 Impact Factor
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ABSTRACT: Evidence from brain imaging studies indicates that white matter volume, density and fractional anisotropy may be altered in individuals with schizophrenia and bipolar disorder. However, the molecular correlates of these deficits remain unknown. In this study we performed a cytoarchitectural assessment of the white matter adjacent to the planum temporale (PT), an auditory association region located within the superior temporal gyrus, in subjects with schizophrenia, bipolar disorder, major depressive disorder and controls (15 subjects per group). Using two-dimensional measures, we recorded the cell density, distribution and size of all neurons and glial nuclei within this region. Glial density was lower in the schizophrenia group, relative to the control group. Neuronal density, neuronal size, and glial nuclear size did not differ between groups. No significant differences in neuronal clustering were observed in the patient groups. Further studies are required to examine whether the observed decrease in glial density within the superior temporal white matter in schizophrenia reflects a deficit in any individual glial cell population.
Biological Psychiatry 10/2009; 115(2-3):156-62. · 8.28 Impact Factor
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Chad A Bousman,
Gursharan Chana,
Stephen J Glatt,
Sharon D Chandler,
Ginger R Lucero,
Erick Tatro,
Todd May,
James B Lohr,
William S Kremen,
Ming T Tsuang, Ian P Everall
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ABSTRACT: Schizophrenia (SCZ) and bipolar disorder (BPD) are polygenic disorders with many genes contributing to their etiologies. The aim of this investigation was to search for dysregulated molecular and cellular pathways for these disorders as well as psychosis. We conducted a blood-based microarray investigation in two independent samples with SCZ and BPD from San Diego (SCZ = 13, BPD = 9, control = 8) and Taiwan (SCZ = 11, BPD = 14, control = 16). Diagnostic groups were compared to controls, and subjects with a history of psychosis [PSYCH(+): San Diego (n = 6), Taiwan (n = 14)] were compared to subjects without such history [PSYCH(-): San Diego (n = 11), Taiwan (n = 14)]. Analyses of covariance comparing mean expression levels on a gene-by-gene basis were conducted to generate the top 100 significantly dysregulated gene lists for both samples by each diagnostic group. Gene lists were imported into Ingenuity Pathway Analysis (IPA) software. Results showed the ubiquitin proteasome pathway (UPS) was listed in the top ten canonical pathways for BPD and psychosis diagnostic groups across both samples with a considerably low likelihood of a chance occurrence (P = 0.001). No overlap in dysregulated genes populating these pathways was observed between the two independent samples. Findings provide preliminary evidence of UPS dysregulation in BPD and psychosis as well as support further investigation of the UPS and other molecular and cellular pathways for potential biomarkers for SCZ, BPD, and/or psychosis.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2009; 153B(2):494-502. · 3.70 Impact Factor
