Association of CAG repeat loci on chromosome 22 with schizophrenia and bipolar disorder

Chromosome 22 has been implicated in schizophrenia and bipolar disorder in a number of linkage, association and cytogenetic studies. Recent evidence has also implicated CAG repeat tract expansion in these diseases. In order to explore the involvement of CAG repeats on chromosome 22 in these diseases, we have created an integrated map of all CAG repeats 5 on this chromosome together with microsatellite markers associated with these diseases using the recently completed nucleotide sequence of chromosome 22. Of the 52 CAG repeat loci identified in this manner, four of the longest repeat stretches in regions previously implicated by linkage analyses were chosen for further study. Three of the four repeat containing loci, were found in the coding region with the CAG repeats coding for glutamine and were expressed in the brain. All the loci studied showed varying degrees of polymorphism with one of the loci exhibiting two alleles of 7 and 8 CAG repeats. The 8-repeat allele at this locus was significantly overrepresented in both schizophrenia and bipolar patient groups when compared to ethnically matched controls, while alleles at the other three loci did not show any such difference. The repeat lies within a gene which shows homology to an androgen receptor related apoptosis protein in rat. We have also identified other candidate genes in the vicinity of this locus. Our results suggest that the repeats within this gene or other genes in the vicinity of this locus are likely to be implicated in bipolar disorder and schizophrenia

The UK Environmental Change Network datasets – integrated and co-located data for long-term environmental research (1993–2015)

Long-term datasets of integrated environmental variables, co-located together, are relatively rare. The UK Environmental Change Network (ECN) was launched in 1992 and provides the UK with its only long-term integrated environmental monitoring and research network for the assessment of the causes and consequences of environmental change. Measurements, covering a wide range of physical, chemical, and biological “driver” and “response” variables are made in close proximity at ECN terrestrial sites using protocols incorporating standard quality control procedures. This paper describes the datasets (there are 19 published ECN datasets) for these co-located measurements, containing over 20 years of data (1993–2015). The data and supporting documentation are freely available from the NERC Environmental Information Data Centre under the terms of the Open Government Licence (see paper for DOIs)

Bi-Directional Effect of Cholecystokinin Receptor-2 Overexpression on Stress-Triggered Fear Memory and Anxiety in the Mouse

Fear, an emotional response of animals to environmental stress/threats, plays an important role in initiating and driving adaptive response, by which the homeostasis in the body is maintained. Overwhelming/uncontrollable fear, however, represents a core symptom of anxiety disorders, and may disturb the homeostasis. Because to recall or imagine certain cue(s) of stress/threats is a compulsory inducer for the expression of anxiety, it is generally believed that the pathogenesis of anxiety is associated with higher attention (acquisition) selectively to stress or mal-enhanced fear memory, despite that the actual relationship between fear memory and anxiety is not yet really established. In this study, inducible forebrain-specific cholecystokinin receptor-2 transgenic (IF-CCKR-2 tg) mice, different stress paradigms, batteries of behavioral tests, and biochemical assays were used to evaluate how different CCKergic activities drive fear behavior and hormonal reaction in response to stresses with different intensities. We found that in IF-CCKR-2 tg mice, contextual fear was impaired following 1 trial of footshock, while overall fear behavior was enhanced following 36 trials of footshock, compared to their littermate controls. In contrast to a standard Yerkes-Dodson (inverted-U shaped) stress-fear relationship in control mice, a linearized stress-fear curve was observed in CCKR-2 tg mice following gradient stresses. Moreover, compared to 1 trial, 36 trials of footshock in these transgenic mice enhanced anxiety-like behavior in other behavioral tests, impaired spatial and recognition memories, and prolonged the activation of adrenocorticotropic hormone (ACTH) and glucocorticoids (CORT) following new acute stress. Taken together, these results indicate that stress may trigger two distinctive neurobehavioral systems, depending on both of the intensity of stress and the CCKergic tone in the brain. A “threshold theory” for this two-behavior system has been suggested

Convergent functional genomic studies of omega-3 fatty acids in stress reactivity, bipolar disorder and alcoholism

Omega-3 fatty acids have been proposed as an adjuvant treatment option in psychiatric disorders. Given their other health benefits and their relative lack of toxicity, teratogenicity and side effects, they may be particularly useful in children and in females of child-bearing age, especially during pregnancy and postpartum. A comprehensive mechanistic understanding of their effects is needed. Here we report translational studies demonstrating the phenotypic normalization and gene expression effects of dietary omega-3 fatty acids, specifically docosahexaenoic acid (DHA), in a stress-reactive knockout mouse model of bipolar disorder and co-morbid alcoholism, using a bioinformatic convergent functional genomics approach integrating animal model and human data to prioritize disease-relevant genes. Additionally, to validate at a behavioral level the novel observed effects on decreasing alcohol consumption, we also tested the effects of DHA in an independent animal model, alcohol-preferring (P) rats, a well-established animal model of alcoholism. Our studies uncover sex differences, brain region-specific effects and blood biomarkers that may underpin the effects of DHA. Of note, DHA modulates some of the same genes targeted by current psychotropic medications, as well as increases myelin-related gene expression. Myelin-related gene expression decrease is a common, if nonspecific, denominator of neuropsychiatric disorders. In conclusion, our work supports the potential utility of omega-3 fatty acids, specifically DHA, for a spectrum of psychiatric disorders such as stress disorders, bipolar disorder, alcoholism and beyond

Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor antagonist SB-399885

Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT₆ receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister-hooded rats (weaned on post-natal day 21-24 and housed individually or in groups of 3-4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a two week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimination (NOD), pre-pulse inhibition of acoustic startle and acquisition, retention and extinction of a conditioned freezing response (CFR) were assessed. Tissue was collected 24 h after the final injection for immunohistochemistry, reverse-phase protein microarray and western blotting. Isolation rearing impaired NOD and cue-mediated CFR, decreased cell proliferation within the dentate gyrus, and elevated hippocampal TNFα levels and Cdc42 expression. SB-399885 reversed the NOD deficit and partially normalized CFR and cell proliferation. These effects were accompanied by altered expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3). Although JNK and p38 themselves were unaltered at this time point hippocampal TAK1 expression and phosphorylation correlated with visual recognition memory in the NOD task. Continued use of this neurodevelopmental model could further elucidate the neurobiology of schizophrenia and aid assessment of novel therapies for drug-resistant cognitive symptoms

Singleton births after routine preimplantation genetic diagnosis using exclusion testing (D4S43 and D4S126) for Huntington's disease

Objective: To develop exclusion testing protocols for Huntington’s disease (HD) linkage markers suitable for use in a clinical preimplantation genetic diagnosis (PGD) setting for couples in whom a partner was at 50% risk of inheriting HD, but who choose not to undergo presymptomatic mutation testing. Design: Preimplantation genetic diagnosis using exclusion testing. Setting: In vitro fertilization clinic. Patient(s): Three couples with family histories of HD, two couples opposed to direct mutation testing. Intervention(s): Development of single-cell polymerase chain reaction tests for PGD for the HD mutation and two HD gene-flanking markers (D4S43 and D4S126), allowing the identification of an individual embryo as being at either low or high risk for developing HD without being diagnostic of the presence of the mutation. Main Outcome Measure(s): D4S43, D4S126, and HD mutation. Result(s): After PGD for HD, couple 1 gave birth to a healthy girl after a frozen embryo transfer, and genetic status was confirmed by prenatal diagnosis to be very low risk for developing HD. Couple 2 gave birth to a healthy boy after their second cycle of PGD, and couple 3, after a third cycle, gave birth to a boy with congenital heart defects, which were successfully corrected with surgery at age 5 days. Both couples 2 and 3 declined prenatal testing, and therefore relinquished the opportunity to confirm the PGD. Conclusion(s): Preimplantation genetic diagnosis for HD using exclusion testing resulted in three live singleton births after six oocyte recovery procedures. The diagnostic protocol provided couples the opportunity to minimize the likelihood of disease transmission to their children, without the requirement for predictive testing.Melinda J. Jasper, Dong Gui Hu, Jan Liebelt, Deborah Sherrin, Robert Watson, Kelton P. Tremellen and Nicole D. Husse

Association of CAG repeat loci on chromosome 22 with schizophrenia and bipolar disorder

Chromosome 22 has, been implicated in schizophrenia and bipolar disorder in a number of linkage, association and. cytogenetic studies. Recent evidence has also implicated CAG repeat tract expansion in these diseases. In order to explore the involvement of CAG repeats on chromosome 22 in these diseases, we have created an integrated map of all CAG repeats greater than or equal to5 on this, chromosome together with microsatellite markers associated with these diseases using the recently completed nucleotide sequence of chromosome 22. Of the 52 GAG repeat loci identified in this, manner, four of the longest repeat stretches in regions previously implicated by linkage analyses were chosen for further study. Three of the four repeat containing loci, were found in the coding region with the CAG repeats coding for glutamine and were expressed In the brain. All. the loci studied showed varying degrees of polymorphism with one of the loci exhibiting two alleles, of 7 and 8 CAG repeats. The 8-repeat allele at this locus was significantly overrepresented in both schizophrenia and bipolar patient groups when compared to ethnically matched controls, while alleles at the other three loci did not show any such difference. The repeat lies within a gene which shows homology to an androgen receptor related apoptosis protein in rat. We have also identified other candidate genes in the vicinity of this locus. Our results suggest that the repeats within this gene or other genes in the vicinity of this locus are, likely to be implicated in bipolar disorder and schizophrenia