BACE1-Deficient Mice Exhibit Alterations in Immune System Pathways.

BACE1 encodes for the beta-site amyloid precursor protein cleaving enzyme 1 or ß-secretase. Genetic deletion of Bace1 leads to behavioral alterations and affects midbrain dopaminergic signaling and memory processes. In order to further understand the role of BACE1 in brain function and behavior, we performed microarray transcriptome profiling and gene pathway analysis in the hippocampus of BACE1-deficient mice compared to wild type. We identified a total of 91 differentially expressed genes (DEGs), mostly enriched in pathways related to the immune and inflammation systems, particularly IL-9 and NF-κB activation pathways. Serum levels of IL-9 were elevated in BACE1-deficient mice. Our network analysis supports an intimate connection between immune response via NF-κB and BACE1 signaling through the NRG1/Akt1 pathway. Our findings warrant future mechanistic studies to determine if BACE1 signaling and the IL-9 pathway interact to alter behavior and brain function. This study opens new avenues in the investigation of hippocampus-related neuroimmunological and neuroinflammation-associated disorders.

Integrated transcriptome and methylome analysis in youth at high risk for bipolar disorder: a preliminary analysis.

First-degree relatives of patients with bipolar disorder (BD), particularly their offspring, have a higher risk of developing BD and other mental illnesses than the general population. However, the biological mechanisms underlying this increased risk are still unknown, particularly because most of the studies so far have been conducted in chronically ill adults and not in unaffected youth at high risk. In this preliminary study we analyzed genome-wide expression and methylation levels in peripheral blood mononuclear cells from children and adolescents from three matched groups: BD patients, unaffected offspring of bipolar parents (high risk) and controls (low risk). By integrating gene expression and DNA methylation and comparing the lists of differentially expressed genes and differentially methylated probes between groups, we were able to identify 43 risk genes that discriminate patients and high-risk youth from controls. Pathway analysis showed an enrichment of the glucocorticoid receptor (GR) pathway with the genes MED1, HSPA1L, GTF2A1 and TAF15, which might underlie the previously reported role of stress response in the risk for BD in vulnerable populations. Cell-based assays indicate a GR hyporesponsiveness in cells from adult BD patients compared to controls and suggest that these GR-related genes can be modulated by DNA methylation, which poses the theoretical possibility of manipulating their expression as a means to counteract the familial risk presented by those subjects. Although preliminary, our results suggest the utility of peripheral measures in the identification of biomarkers of risk in high-risk populations and further emphasize the potential role of stress and DNA methylation in the risk for BD in youth.

Newer insights into the role of miRNA a tiny genetic tool in psychiatric disorders: focus on post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a mental disorder occurring in about 2-9% of individuals after their exposure to life-threatening events, such as severe accidents, sexual abuse, combat or a natural catastrophe. Because PTSD patients are exposed to trauma, it is likely that epigenetic modifications have an important role in disease development and prognosis. For the past two decades, abnormal expression of the epigenetic regulators microRNAs (miRs) and miR-mediated gene regulation have been given importance in a variety of human diseases, such as cancer, heart disease and viral infection. Emerging evidence supports a role for miR dysregulation in psychiatric and neurological disorders, including schizophrenia, bipolar disorder, anxiety, major depressive disorder, autism spectrum disorder and Tourette's syndrome. Recently mounting of evidence supports the role of miR both in preclinical and clinical settings of psychiatric disorders. Abnormalities in miR expression can fine-tune the expression of multiple genes within a biological network, suggesting that miR dysregulation may underlie many of the molecular changes observed in PTSD pathogenesis. This provides strong evidence that miR not only has a critical role in PTSD pathogenesis, but can also open up new avenues for the development of diagnostic tools and therapeutic targets for the PTSD phenotype. In this review, we revisit some of the recent evidence associated with miR and PTSD in preclinical and clinical settings. We also discuss the possible clinical applications and future use of miRs in PTSD therapy.

Physiological and behavioral effects of amphetamine in BACE1(-/-) mice.

ß-Site APP-cleaving Enzyme 1 (BACE1) is a protease that has been linked to schizophrenia, a severe mental illness that is potentially characterized by enhanced dopamine (DA) release in the striatum. Here, we used acute amphetamine administration to stimulate neuronal activity and investigated the neurophysiological and locomotor-activity response in BACE1-deficient (BACE1(-/-) ) mice. We measured locomotor activity at baseline and after treatment with amphetamine (3.2 and 10 mg/kg). While baseline locomotor activity did not vary between groups, BACE1(-/-) mice exhibited reduced sensitivity to the locomotor-enhancing effects of amphetamine. Using high-performance liquid chromatography (HPLC) to measure DA and DA metabolites in the striatum, we found no significant differences in BACE1(-/-) compared with wild-type mice. To determine if DA neuron excitability is altered in BACE1(-/-) mice, we performed patch-clamp electrophysiology in putative DA neurons from brain slices that contained the substantia nigra. Pacemaker firing rate was slightly increased in slices from BACE1(-/-) mice. We next measured G protein-coupled potassium currents produced by activation of D2 autoreceptors, which strongly inhibit firing of these neurons. The maximal amplitude and decay times of D2 autoreceptor currents were not altered in BACE1(-/-) mice, indicating no change in D2 autoreceptor-sensitivity and DA transporter-mediated reuptake. However, amphetamine (30 µm)-induced potassium currents produced by efflux of DA were enhanced in BACE1(-/-) mice, perhaps indicating increased vesicular DA content in the midbrain. This suggests a plausible mechanism to explain the decreased sensitivity to amphetamine-induced locomotion, and provides evidence that decreased availability of BACE1 can produce persistent adaptations in the dopaminergic system.

Childhood maltreatment and inflammatory markers: a systematic review.

OBJECTIVE: Childhood maltreatment (CM) has been associated with several diseases in adult life, including diabetes, obesity and mental disorders. Inflammatory conditions have been postulated as possible mediators of this relationship. The aim was to conduct a systematic review regarding the association between CM and inflammatory markers in adulthood. METHOD: A literature search of the PubMed, ISI, EMBASE and PsychINFO databases was conducted. The key terms used were as follows: 'Child Maltreatment', 'Childhood Trauma', 'Early Life Stress', 'Psychological Stress', 'Emotional Stress', 'Child Abuse' and 'Child Neglect'. They were cross-referenced separately with the terms: 'C-reactive Protein (CRP)', 'Tumor Necrosis Factor', 'Cytokine', 'Interleukin', 'Inflammatory' and 'Inflammation'. RESULTS: Twenty articles remained in the review after exclusion criteria were applied. Studies showed that a history of CM was associated with increased levels of CRP, fibrinogen and proinflammatory cytokines. Increased levels of circulating CRP in individuals with a history of CM were the most robust finding among the studies. Data about anti-inflammatory mediators are still few and inconsistent. CONCLUSION: Childhood maltreatment is associated with a chronic inflammatory state independent of clinical comorbidities. However, studies are heterogeneous regarding CM assessment and definition. Important methodological improvements are needed to better understand the potential impact of CM on inflammatory response.

TGFB-induced factor (TGIF): a candidate gene for psychosis on chromosome 18p.

Schizophrenia (SC) and bipolar disorder (BP) share many clinical features, among them psychosis. We previously identified a putative gene locus for psychosis on chromosome 18p in a sample from the Central Valley of Costa Rica (CVCR) population. The present study replicated the association to a specific allele of microsatellite marker D18S63 on 18p11.3, using a newly collected sample from the CVCR. A combined analysis of both samples, plus additional subjects, showed that this specific allele on D18S63, which lies within an intron on the TGFB-induced factor (TGIF) gene, is strongly associated (P-value=0.0005) with psychosis. Eleven additional SNP markers, spanning five genes in the region, were analyzed in the combined sample from the CVCR. Only the four SNPs within the TGIF gene were in strong linkage disequilibrium with D18S63 (D'=1.00). A specific haplotype for all five markers within the TGIF gene showed evidence of association (P-value=0.011) to psychosis. A second, distinct haplotype, containing a newly identified nonsynonymous polymorphism in exon 5 of the TGIF gene, showed a nonsignificant trend towards association to psychosis (P-value=0.077). TGIF is involved in neurodevelopment, neuron survival and controls the expression of dopamine receptors. Altogether, our results point to the possible involvement of TGIF in the pathophysiology of psychotic disorders in the CVCR population.

Association analyses of the neuregulin 1 gene with schizophrenia and manic psychosis in a Hispanic population.

OBJECTIVE: This study used the population of the Central Valley of Costa Rica (CVCR) and phenotyping strategies alternative to DSMIV classifications to investigate the association of neuregulin 1 with schizophrenia. METHOD: Using 134 family trios with a history of psychosis, we genotyped six of the seven markers originally identified to be associated with schizophrenia in Iceland. RESULTS: The neuregulin Icelandic haplotype was not associated with schizophrenia in the CVCR population. However, a novel haplotype was found to be overrepresented in subjects with functional psychosis (global P-value > 0.05). Stratification of the sample by history of mania suggests that this haplotype may be preferentially over-transmitted to persons with a history of manic psychosis. CONCLUSION: These results suggest that the neuregulin 1 gene is unlikely to play a major role in predisposing to schizophrenia in the CVCR. Further studies in the CVCR and other Latin American populations should be performed in order to corroborate these findings.

Interaction of the betaIV-tubulin isotype with actin stress fibers in cultured rat kidney mesangial cells.

Microtubules and actin filaments are two of the major components of the cytoskeleton. There is accumulating evidence for interaction between the two networks. Both the alpha- and beta-subunits of tubulin exist as numerous isotypes, some of which have been highly conserved in evolution. In an effort to better understand the functional significance of tubulin isotypes, we used a double immunofluorescence labeling technique to investigate the interactions between the tubulin beta-isotypes and the actin stress fiber network in cultured rat kidney mesangial cells, smooth-muscle-like cells from the renal glomerulus. Removal of the soluble cytoplasmic and nucleoplasmic proteins by detergent extraction caused the microtubule network to disappear while the stress fiber network was still present. In these extracted cells, the betaI- and betaII-tubulin isotypes were no longer present in the cytoplasm while the betaIV-isotype co-localized with actin stress fibers. Co-localization between betaIV-tubulin and actin stress fibers was also observed when the microtubule network was disrupted by the anti-tubulin drug colchicine and also by microinjection of the betaIV-tubulin antibody. Our results suggest that the betaIV isotype of tubulin may be involved in interactions between microtubules and actin.

Mechanism of localization of betaII-tubulin in the nuclei of cultured rat kidney mesangial cells.

Tubulin is an alphabeta heterodimer. Both the alpha and beta polypeptides exist as multiple isotypes. Although tubulin was generally thought to exist only in the cytoplasm, we have previously reported the presence of the betaII isotype of tubulin in the nuclei of cultured rat kidney mesangial cells, smooth-muscle-like cells that reside in the glomerular mesangium; nuclear betaII exists as an alphabetaII dimer, capable of binding to colchicine, but in non-microtubule form [Walss et al., 1999: Cell Motil. Cytoskeleton 42:274-284]. We have now investigated the nature of the process by which alphabetaII enters the nuclei of these cells. By micro-injecting fluorescently labeled alphabetaII into mesangial cells, we found that alphabetaII was present in the nuclei of cells only if they were allowed to go through mitosis. In contrast, there were no circumstances in which microinjected fluorescently labeled abetaII or alphabetaIV dimers entered the nuclei. These findings, together with the absence of any nuclear localization signal in alphabetaII, strongly favor the model that alphabetaII, rather than being transported into the intact nucleus, co-assembles with the nucleus at the end of mitosis. Our results also indicate that the nuclear localization mechanism is specific for alphabetaII. This result raises the possibility that alphabetaII may have a specific function that requires its presence in the nuclei of cultured rat kidney mesangial cells.