Showing papers by "Thomas Werge published in 2006"

Schizophrenia and Oxidative Stress: Glutamate Cysteine Ligase Modifier as a Susceptibility Gene

Abstract: Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study GCLM gene expression is decreased in patients' fibroblasts Thus, GSH metabolism dysfunction is proposed as one of the vulnerability factors for schizophrenia

GABA(A) receptor function is regulated by lipid bilayer elasticity.

Abstract: Docosahexaenoic acid (DHA) and other polyunsaturated fatty acids (PUFAs) promote GABA(A) receptor [(3)H]-muscimol binding, and DHA increases the rate of GABA(A) receptor desensitization. Triton X-100, a structurally unrelated amphiphile, similarly promotes [(3)H]-muscimol binding. The mechanism(s) underlying these effects are poorly understood. DHA and Triton X-100, at concentrations that affect GABA(A) receptor function, increase the elasticity of lipid bilayers measured as decreased bilayer stiffness using gramicidin channels as molecular force transducers. We have previously shown that membrane protein function can be regulated by amphiphile-induced changes in bilayer elasticity and hypothesized that GABA(A) receptors could be similarly regulated. We therefore studied the effects of four structurally unrelated amphiphiles that decrease bilayer stiffness (Triton X-100, octyl-beta-glucoside, capsaicin, and DHA) on GABA(A) receptor function in mammalian cells. All the compounds promoted GABA(A) receptor [(3)H]-muscimol binding by increasing the binding capacity of high-affinity binding without affecting the associated equilibrium binding constant. A semiquantitative analysis found a similar quantitative relation between the effects on bilayer stiffness and [(3)H]-muscimol binding. Membrane cholesterol depletion, which also decreases bilayer stiffness, similarly promoted [(3)H]-muscimol binding. In whole-cell voltage-clamp experiments, Triton X-100, octyl-beta-glucoside, capsaicin, and DHA all reduced the peak amplitude of the GABA-induced currents and increased the rate of receptor desensitization. The effects of the amphiphiles did not correlate with the expected changes in monolayer spontaneous curvature. We conclude that GABA(A) receptor function is regulated by lipid bilayer elasticity. PUFAs may generally regulate membrane protein function by affecting the elasticity of the host lipid bilayer.

Association Between the CCR5 32-bp Deletion Allele and Late Onset of Schizophrenia

Abstract: OBJECTIVE: The 32-bp deletion allele in chemokine receptor CCR5 has been associated with several immune-mediated diseases and might be implicated in schizophrenia as well. METHOD: The authors genotyped DNA samples from 268 schizophrenia patients and 323 healthy subjects. Age at first admission to a psychiatric hospital department served as a measure of disease onset. RESULTS: Patients and comparison subjects differed marginally in their genotype distribution, with a slightly higher frequency of the deletion allele seen in the patients. The authors found the deletion allele to be associated with higher age at first admission. After age at first admission was analyzed as a continuous variable, it was dichotomized using 40 years as the cutoff. With this approach the authors found that genotype distributions of patients with age at first admission above the cutoff (possible cases of late-onset schizophrenia) and healthy subjects differed significantly. This was reflected in an increased frequency of the delet...

Estrogen receptor alpha and risk for cognitive impairment in postmenopausal women.

Abstract: The estrogen receptor alpha (ESR1) gene has been implicated in the process of cognitive impairment in elderly women. In a paired case-control study, we tested whether two ESR1 gene polymorphisms (the XbaI and PvuII sites) are risk factors for cognitive impairment as measured by the six-item Orientation-Memory-Concentration test in postmenopausal Danish women. Hormone replacement therapy, age and executive cognitive ability were examined as covariates for ESR1 gene effects on cognitive impairment. The XbaI polymorphism showed a marginal effect on cognitive abilities (P=0.054) when adjusted for executive cognitive ability. Using a dominant genetic model for the X allele, we found an elevated risk (executive cognitive ability adjusted P=0.033) for cognitive impairment. Hormone replacement therapy also had a borderline effect on cognitive ability (P=0.049) and this effect was reflected in executive cognitive ability. These data support that the ESR1 gene variants affect cognitive functioning in postmenopausal women.

No association between the −399 C>T polymorphism of the neuropeptide Y gene and schizophrenia, unipolar depression or panic disorder in a Danish population

Abstract: Objective: A polymorphism in the promoter region of the NPY gene at position −399 C>T was recently reported to be associated with schizophrenia in a Japanese population and with treatment refractory unipolar depression in a Swedish population. The objective of this study was to investigate potential associations between the polymorphism and three psychiatric disorders in a Danish population. Method: We investigated the occurrence of the polymorphism in patients with schizophrenia (n = 291), unipolar depression (n = 256) and panic disorder (n = 142) compared with controls (n = 716). Results: We detected the polymorphism −399 C>T at a frequency of 48% in controls. No significant differences were found between genotype or allele frequencies in controls vs. the patient groups. Conclusion: The lack of association between the −399 C>T polymorphism and schizophrenia, unipolar depression or panic disorder, respectively, suggests that the polymorphism is not involved in the etiology of these disorders in the Danish population.

Effects of the cannabinoid CB1 receptor agonist CP55,940 and antagonist SR141716A on d-amphetamine-induced behaviours in Cebusmonkeys:

Abstract: Several clinical studies have shown that alterations in the cannabinoid system in the brain may be associated with schizophrenia. Although evidence points towards an antipsychotic potential for can...

Apolipoprotein D is associated with long-term outcome in patients with schizophrenia

Abstract: Accumulating evidence implicates deficiencies in apolipoprotein D (ApoD) function and arachidonic acid signaling in schizophrenic disorders. We addressed two hypotheses in relation to ApoD: first, polymorphisms in the ApoD gene confer susceptibility to or are markers of disease, and, second, genetic variation in the ApoD is associated with long-term clinical outcome to antipsychotic treatment. We genotyped two single-nucleotide polymorphisms in the ApoD gene in 343 chronic patients with schizophrenia spectrum disorders (ICD-10) and 346 control subjects of Danish origin. We did not find ApoD alleles, genotypes or haplotypes to be associated with disease. However, we did find that long-term clinical outcome was associated with the ApoD polymorphism rs7659 (P=0.041) following adjustment for lifetime clinical global impression, age at first admission and gender.

Cognitive impairment in elderly women: the relative importance of selected genes, lifestyle factors, and comorbidities.

Abstract: BACKGROUND A variety of factors contribute to the development of cognitive impairment in elderly people. Previous studies have focused upon a single or a few risk factors. In this study we assessed and compared the significance of a wide variety of potential risk factors for cognitive impairment in postmenopausal women. METHODS A total of 208 pairs of elderly women (mean age = 73.2 years) were examined in a cross-sectional case-control study. Each pair consisted of a case (with impaired cognition) and a control subject matched by age and educational status. Cognitive functions were determined using a modified version of the Blessed test. Participants were also subjected to a general clinical examination and they were interviewed to collect information on lifestyle practices and comorbid disorders. Genotypes for the apolipoprotein E (APOE) epsilon4, catechol-O-methyltransferase (COMT) Val/Met, and brain-derived neurotropic growth factor (BDNF) Val/Met polymorphisms were determined. Data were analyzed by conditional logistic regression. RESULTS We identified a set of risk factors for age-related cognitive impairment. A statistical model for assessment of the importance of these factors was constructed. The factors in this model were physical exercise (odds ratio [OR] = 0.50, 95% confidence interval [CI] = 0.32-0.78), regular alcohol consumption (OR = 0.49, 95% CI = 0.29-0.83), metabolic syndrome (OR = 2.83, 95% CI = 1.26-6.39), depression (OR = 3.24, 95% CI = 1.28-8.22), and the APOE epsilon4 allele (OR = 1.76, 95% CI = 1.09-2.83). Also COMT genotype was present as a risk factor in the statistical model (p = 0.08). CONCLUSIONS Lifestyle risk factors, comorbid disorders, and genetic factors contribute to development of age-related cognitive impairment. The two former groups of risk factors appear to be particular important in this respect.

The substituted (S)-3-phenylpiperidine (-)-OSU6162 reduces apomorphine- and amphetamine-induced behaviour in Cebus apella monkeys.

Abstract: Low affinity dopamine (DA) D2 antagonists such as the substituted (S)-3-phenylpiperidine (−)-OSU6162 have been proposed to be putative antipsychotic agents not endowed with extrapyramidal side effects (EPS). In the present study we investigated the effects of (−)-OSU6162 on (−)-apomorphine and d-amphetamine-induced behaviours in EPS sensitised Cebus apella monkeys. (−)-OSU6162 was administered subcutaneously in doses of 1, 3, 6 and 9 mg/kg alone and in combination with (−)-apomorphine (0.25 mg/kg) or d-amphetamine (0.5 mg/kg). (−)-OSU6162 inhibited (−)-apomorphine-(1–9 mg/kg) as well as d-amphetamine (3–9 mg/kg)-induced arousal and stereotypy. EPS did not occur when (−)-OSU6162 was administered in combination with (−)-apomorphine or d-amphetamine. However, when (−)-OSU6162 was administered alone, dystonia was observed at high doses (6 and 9 mg/kg) in two out of six monkeys. The present study shows that (−)-OSU6162 can inhibit (−)-apomorphine-induced behaviours in non-human primates at doses that do not cause EPS. When (−)-OSU6162 was tested against d-amphetamine-induced behaviours a separation between dose levels that inhibit d-amphetamine effects and cause EPS was not observed. The data further substantiate a role for low affinity DA D2 antagonists in the pharmacological treatment of psychosis.

Identification and Characterization of a Tandem Repeat in Exon III of the Dopamine Receptor D4 (DRD4) Gene in Cetaceans

Abstract: Alargenumberofmammalianspeciesharboratandemrepeat inexonIIIofthegeneencodingdopaminereceptorD4(DRD4), a receptor associated with cognitive functions. In this study, a DRD4 gene exon III tandem repeat from the order Cetacea was identified and characterized. Included in our study were samplesfrom10 white-beakeddolphins(Lagenorhynchus albirostris), 10 harbor porpoises (Phocoena phocoena), eight sperm whales(Physeter macrocephalus),andfiveminkewhales(Balaenoptera acutorostrata). Using enzymatic amplification followed by sequencing of amplified fragments, a tandem repeat composed of 18-bp basic units was detected in all of these species. The tandem repeats in white-beaked dolphin and harbor porpoisewerebothmonomorphicandconsistedof11and12basic units, respectively. In contrast, the sperm whale harbored a polymorphic tandem repeat with size variants composed of three, four, and five basic units. Also the tandem repeat in minke whale was polymorphic; size variants composed of 6 or 11 basic units were found in this species. The consensus sequencesofthebasicunitswereidenticalinthecloselyrelated white-beaked dolphin and harbor porpoise, and these sequences differed by a maximum of two changes when compared to the remaining species. There was a high degree of similaritybetweenthecetaceanbasicunitconsensussequences and those from members of the horse family and domestic cow, which also harbor a tandem repeat composed of 18bp basic units in exon III of their DRD4 gene. Consequently, the 18-bp tandem repeat appears to have originated prior to the differentiation of hoofed mammals into odd-toed and even-toed ungulates. The composition of the tandem repeat in cetaceans differed markedly from that in primates, which is composed of 48-bp repeat basic units.

Genetic vulnerability factor for schizophrenia: association with glutamate cysteine ligase modifier gene and abnormal enzyme activity

Abstract: Background: We previously reported in schizophrenia patients a decreased level of glutathione ([GSH]), the principal non-protein antioxidant and redox regulator, both in cerebrospinal-fluid and prefrontal cortex To identify possible genetic causation, we studied genes involved in GSH metabolism Methods: Genotyping: mass spectrometry analysis of polymerase chain reaction (PCR) amplified DNA fragments purified from peripheral blood Gene expression: real-time PCR of total RNA isolated from fibroblast cultures derived from skin of patients (DSM-IV) and healthy controls (DIGS) Results: Case-control association study of single nucleotide polymorphisms (SNP) from the GSH key synthesizing enzyme glutamate-cysteine-ligase (GCL) modifier subunit (GCLM) was performed in two populations: Swiss (patients/controls: 40/31) and Danish (349/348) We found a strong association of SNP rs2301022 in GCLM gene (Danish: c2=32; P=0001 after correction for multiple testing) Evidence for GCLM as a risk factor was confirmed in linkage study of NIMH families Moreover, we observed a decrease in GCLM mRNA levels in patient fibroblasts, consistently with the association study Interestingly, Dalton and collaborators reported in GCLM knock-out mice an increased feedback inhibition of GCL activity, resulting in 60% decrease of brain [GSH], a situation analogous to patients These mice also exhibited an increased sensitivity to oxidative stress Similarly, under oxidative stress conditions, GCL enzymatic activity was also decreased in patient fibroblasts Conclusions: These results at the genetic and functional levels, combined with observations that GSH deficient models reveal morphological, electrophysiological, and behavioral anomalies analogous to those observed in patients, suggest that GCLM allelic variant is a vulnerability factor for schizophrenia