ORIGINAL RESEARCH ARTICLES
Dopamine D2/D3-receptor and transporter densities in nucleus accumbens and amygdala of type 1 and 2 alcoholics
E Tupala, H Hall, K Bergström, T Särkioja, P Räsänen, T Mantere, J Callaway, J Hiltunen, J Tiihonen
Alcohol acts through mechanisms involving the brain neurotransmitter dopamine (DA) with the nucleus accumbens as the key zone for mediating these effects. The authors evaluated the densities of DA D2/D3 receptors and transporters in the nucleus accumbens and amygdala of Cloninger type 1 and 2 alcoholics and healthy controls. When compared with controls, the mean density of DA D2/D3 receptors was 20% lower in the nucleus accumbens and 41% lower in the amygdala, and the mean density of DA transporters in the nucleus accumbens was 39% lower in type 1 alcoholics. These data indicate that dopaminergic functions in these limbic areas may be impaired among type 1 alcoholics, due to the substantially lower number of receptor sites. The authors' results suggest that such a reduction may result in the chronic overuse of alcohol as an attempt to stimulate DA function.
Suicide attempts and the tryptophan hydroxylase gene
M Abbar, P Courtet, F Bellivier, M Leboyer, JP Boulenger, D Castelnau, M Ferreira, C Lambercy, D Mouthon, A Paoloni-Giacobino, M Vessaz, A Malafosse, C Buresi
A specific genetic vulnerability for suicidal behavior is strongly suggested by the results of epidemiological genetics studies. Several lines of evidence suggest that regulation of serotonin neurotransmission is a key factor for this vulnerability. Recent studies have investigated the involvement of the gene coding for the tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, in the genetic susceptibility to suicidal behavior. In this case-control study, the authors investigated seven polymorphisms spanning the entire TPH gene in 231 suicide attempters and 281 controls. Significant associations were found between variants within the 3' noncoding region and suicide attempt. The association was strongest for subjects who had attempted suicide by violent means and who had a history of major depression. The results presented here, and those of previous studies, suggest that a genetic variant of the 3' part of the TPH gene may be a susceptibility factor for a phenotype combining suicidal behavior, mood disorder and impulsive aggression.
Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients
SR Rice, N Niu, DB Berman, LL Heston, JL Sobell
Schizophrenia is a severe, chronic brain disorder affecting cognition and behavior that affects approximately 1% of the worldwide population. While the causes of the disorder are unknown, genetic factors are believed to play a role in the disease. In this study, the authors examined the gene coding for the main subunit of the N-methyl-D-aspartate (NMDA) receptor to determine whether there are differences between schizophrenic patients and normal individuals. Each NMDA receptor is made up of at least two of the main subunits, coded for by the NR1 gene, along with two other subunits that seem to modulate the activity of the NR1 subunits. This multiunit NMDA receptor binds glutamate and excites brain cells. This results in a cascade of other brain signals that are crucial for brain development and plasticity over time. Interestingly, the NMDA receptor also binds the illicit drug phencyclidine (PCP) which causes a schizophrenia-like reaction in normal individuals and exacerbates the disease symptoms in patients. Additionally, a mouse model of schizophrenia was recently created by reducing the expression of the main subunit, NR1, of the NMDA receptor in the animals. However, when the authors examined the NR1 subunit gene in schizophrenic patients, no changes were found that would be likely to disrupt the proper functioning of the receptor. Thus, these findings do not support a role for the NR1 subunit gene in the development of schizophrenia.
Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia
R Molteni, BK Lipska, DR Weinberger, G Racagni,MA Riva
Schizophrenia is a complex disorder characterized by hallucinations, delusions and cognitive deficits, which can be the result of adverse circumstances taking place during brain development. Since early life events can set the stage for long-term impairment in brain function and plasticity, animal models should be able to reproduce these events in order to allow the investigation of the molecular systems that contribute to schizophrenia-related dysfunction. The authors report that a lesion of the ventral hippocampus during early postnatal life, a paradigm that recapitulated fundamental features of schizophrenia, alters the expression and stress-induced modulation of neurotrophic factors, which are important players in brain development and cellular plasticity. These changes might contribute to permanent structural and functional alterations leading to an increased vulnerability for psychiatric diseases.
Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia
K Mirnics, FA Middleton, GD Stanwood, DA Lewis, P Levitt
Using cDNA microarrays, the author discovered that the gene encoding an important intracellular signaling protein, regulator of G-protein signaling 4 (RGS4), was the most consistently and significantly decreased transcript in the prefrontal cortex of the schizophrenic subjects they examined. The expression levels of ten other RGS family members and 274 genes associated with G-protein signaling represented on the microarrays were unchanged. Quantitative in situ hybridization verified the microarray RGS4 data, and demonstrated highly correlated decreases in RGS4 expression in subjects with schizophrenia across the prefrontal, motor and visual cortices. RGS4 expression was not altered in the prefrontal cortex of subjects with major depressive disorder or in an animal model of antipsychotic exposure. The combined data indicate that a decrease in RGS4 expression may be a common and specific feature of schizophrenia, which could be due either to genetic factors or a disease-specific adaptation, both of which could affect neuronal signaling.
A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree
J Meyer, A Huberth, G Ortega, YV Syagailo, S Jatzke, R Mössner, TM Strom, I Ulzheimer-Teuber, G Stöber, A Schmitt, KP Lesch
Schizophrenia is a common and etiologically heterogeneous disorder. Although inheritance of schizophrenic syndromes is complex with genetic and environmental factors contributing to the clinical phenotype, some familial subtypes of catatonic schizophrenia, appear to be transmitted in an autosomal dominant manner. The authors report that a Leu309Met mutation in WKL1, a positional candidate gene on chromosome 22q13.33 encoding a putative non-selective cation channel expressed exclusively in brain, co-segregates with catatonic schizophrenia in an extended pedigree. Structural analyses revealed that this missense mutation results in conformational changes of the mutant protein. The results not only underscore the importance of genetic mechanisms in the etiology of schizophrenic syndromes, but also provide a better understanding of the pathogenesis and incapacitating course of catatonic schizophrenia and related disorders.
Schizophrenic women with the APOE  4 allele have a worse prognosis than those without it
L Martorell, C Virgos, J Valero, G Coll, L Figuera, J Joven, M Pocoví, A Labad, E Vilella
The  4 allele of APOE is a risk factor in Alzheimer's disease and has been related to other neuropsychiatric disorders including schizophrenia. The authors carried out an association study to compare the APOE common variant in schizophrenia patients and controls and found no differences in genotype distributions or allele frequencies between the groups. In the group of patients, they also analysed the possible influence of the 4 allele in the clinical variables. Age at onset of 4+ schizophrenic women is 4 years earlier than that of 4- women and their risk of suffering a negative syndrome subtype is four times greater. This was not found in schizophrenic men. The authors' results show that the APOE variant is not a risk factor for developing schizophrenia but that it may modulate its phenotypic expression in a sex-dependent manner.
The genomic organisation of the metabotropic glutamate receptor subtype 5 gene and its association with schizophrenia
RS Devon, S Anderson, P Teague, WJ Muir, V Murray, AJ Pelosi, DHR Blackwood, DJ Porteous
The biological function of metabotropic glutamate recetor subtype 5 gene (GRM5) has been linked to the regulation of brain functions that are thought to be disturbed in schizophrenia. The authors have established that the GRM5 gene is tightly linked to a chromosome rearrangement which co-segregates with schizophrenia in a large Scottish family. Here, the authors show by comparing a large cohort of schizophrenic patients with matched controls an association between a newly discovered DNA sequence variation and the disorder (P = 0.04). This suggests that altered function of the GRM5 gene is a potential risk factor in schizophrenia.
Exon 3 of tyrosine hydrolase gene: lack of association with Japanese schizophrenia patients
M Ota, A Nakashima, K Ikemoto, S Nojima, M Tanaka, M Okuda, H Koga, K Mori, YS Kaneko, K Fujiwara, H Yamamoto, T Nagatsu, A Ota
Exon 3 of the human tyrosine hydroxylase (TH) gene encodes the sequence from Ser31 to Glu104 of type 1 enzyme, which sequence contains the critical parts for the regulation of the catalytic activity. The amino acid residues Gly36-Arg37-Arg38 were identified as a key sequence for dopamine (DA) to exert its inhibitory effect on TH catalytic activity. Therefore, the authors screened the nucleotide sequences of exon 3 from 201 Japanese patients with schizophrenia to explain the elevation in the synaptic or presynaptic DA concentrations in schizophrenic brain. However, no mutated sequences of exon 3 and both exon-intron boundaries were detected in any of the patients examined. Polymorphism generating Val81 and Met81 were compared between 201 patients and 175 Japanese healthy controls, which did not suggest an association between the polymorphism and schizophrenia. These results indicate that exon 3 of the human TH gene lacks association with schizophrenia in Japanese patients.
Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3  gene and promoter in late onset Alzheimer's disease
C Russ, S Lovestone, JF Powell
Alzheimer's disease (AD) is the most common form of progressive neurodegenerative dementia. Neurofibrillary tangles (NFT), a major pathological hallmark of AD, are comprised of paired helical filaments formed from aberrantly phosphorylated microtubule associated protein tau. Glycogen synthase kinase 3 beta (GSK3 ) phosphorylates tau at sites that are abnormally phosphorylated in AD. GSK3 interacts with presenilin 1 and plays a role in wnt and insulin signalling cascades, the disruption of which has been suggested to be associated with AD. Moreover GSK3 activity appears to be altered in AD brain. The authors sought to identify sequence variations in the gene and its promoter, as these could have an effect on activity and expression of GSK3. DNA sequencing of the GSK3 gene and its putative promoter revealed several sequence variations, however on further examination none of these, either alone or in synergy, showed any association with AD. These results suggest that the aberrant phosphorylation of tau by GSK3 in AD is not due to effect of sequence variations in the gene or its promoter.
Association between an agouti-related protein gene polymorphism and anorexia nervosa
T Vink, A Hinney, AA van Elburg, SHM van Goozen, LA Sandkuijl, RJ Sinke, BM Herpertz-Dahlmann, J Hebebrand, H Remschmidt, H van Engeland, RAH Adan
Anorexia nervosa (AN) is a dramatic disease with a high degree of mortality. Family studies suggested a strong genetic component in AN. The authors demonstrate for the first time an association between a mutation in a gene, Agouti-related Protein (AgRP), and AN. AgRP stimulates food intake when injected into brains of rats and mice, because AgRP suppresses melanocortin receptor activity. Genetic studies in humans and mice demonstrated that decreased activity of melanocortin receptors is associated with obesity. The authors' finding suggests that the opposite occurs when there is increased melanocortin receptor activity: inadequate suppression of melanocortin receptors by (mutated) AgRP increases the susceptibility to develop AN.
Low avidity of human serum antibodies for Borna disease virus antigens questions their diagnostic value
U Allmang, M Hofer, S Herzog, K Bechter, P Staecheli
Certain forms of human psychiatric disorders are believed to result from infection with Borna disease virus mainly because antibodies recognizing viral antigens were found more frequently in sera of psychiatric patients than in healthy individuals. The authors report that human antibodies bind Borna disease virus antigen with much lower avidity than antibodies from animals with autopsy-confirmed Borna disease. Reactive human antibodies persisted for many years without gaining affinity, suggesting that they are cross-reactive and were probably induced by an antigenically related agent of unknown identity. The authors conclude that the presence of serum antibodies with the above-described properties should not be taken as solid proof of infection with Borna disease virus. Their results call for a careful re-evaluation of previous epidemiological data, which indicated that this virus is a human pathogen.
Attention-deficit hyperactivity disorder and the adrenergic receptors a1C and a2C
CL Barr, K Wigg, G Zai, W Roberts, M Malone, R Schachar, R Tannock, JL Kennedy
The adrenergic system has been hypothesized to be involved in attention-deficit hyperactivity disorder (ADHD) based on pharmacological treatments and animal models. Noradrenergic neurons are implicated in the modulation of vigilance, improvement of visual attention, initiation of adaptive response, learning and memory. In this study the authors tested the genes for two adrenergic receptors, a1C (ADRA1C) located on chromosome 8p11.2, and a2C (ADRA2C) located on chromosome 4p16, as genetic susceptibility factors in ADHD. For the adrenergic receptor a1C they used a C to T polymorphism that results in a change of Cys to Arg at codon 492 for the linkage study. For the adrenergic receptor a2C gene they examined a dinucleotide repeat polymorphism located approximately 6 kb from the gene. The authors examined these polymorphisms in a sample of 103 families ascertained through an ADHD proband. They did not observe any evidence for linkage of these genes and ADHD.
Association between violent suicidal behavior and the low activity allele of the serotonin transporter gene
P Courtet, P Baud, M Abbar, JP Boulenger, D Castelnau, D Mouthon, A Malafosse, C Buresi
There is compelling evidence that serotonin system dysfunction is associated with suicidal behavior. Some data suggest that this association is stronger with violent suicidal behavior. The genetic susceptibility to suicidal behavior may involve a functional polymorphism (S/L alleles) in the promoter region of the serotonin transporter gene. The S allele of this gene has been found to be associated with a lower level of expression of the gene and lower levels of 5-HT uptake. The authors genotyped 51 violent suicide attempters and 139 controls with no history of suicidal behavior, both from West European Caucasian origin. The frequencies of the S allele and the SS genotype were significantly higher in the violent suicide attempters than in the controls. The odds ratio for the SS genotype vs the LL genotype was 3.63 (95% CI (1.27-10.40)). Together with previous reports, the present finding suggests that a change in expression of the gene encoding the 5-HT transporter may be involved in violent suicide behavior.
A susceptibility locus for bipolar affective disorder in chromosomal region 10q25-q26
S Cichon, G Schmidt-Wolf, J Schumacher, DJ Müller, M Hürter, TG Schulze, M Albus, M Borrmann-Hassenbach, E Franzek, M Lanczik, J Fritze, R Kreiner, B Weigelt, J Minges, D Lichtermann, B Lerer, K Kanyas, K Strauch, C Windemuth, MP Baur, TF Wienker, W Maier, M Rietschel, P Propping, MM Nöthen
In an attempt to identify susceptibility loci for bipolar affective disorder, the authors are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. Here, they present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers provided evidence for linkage at chromosomal region 10q25-q26. The putative susceptibility locus could be localized to an interval of approximately 15 cM between markers D10S1483 and D10S217. Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26.
Allelic variation of serotonin transporter expression is associated with depression in Parkinson's disease
R Mossner, A Henneberg, A Schmitt, YV Syagailo, M Grassle, T Hennig, R Simantov, M Gerlach, P Riederer, KP Lesch
Parkinson's disease (PD) is the second most common neurodegenerative disease. Depression is a frequent and often presymptomatic feature of PD. Moreover, there is degeneration of serotonin neurons and loss of the serotonin transporter (5HTT) in PD. The authors therefore assessed a functional polymorphism in the promoter of the 5HTT gene in idiopathic PD patients. They found that this polymorphism does not represent a risk factor for development of PD. However, this polymorphism was associated with depressive symptomatology in PD patients. Together with other genetic markers yet to be described, it could be possible in the future to pinpoint those PD patients most at risk for developing depression.
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