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K Fuchs

Publications and source records attributed to K Fuchs.

At least 55 records · Page 3Linked to original sources
PubMed1999

Structure and subunit composition of GABA(A) receptors.

GABA(A) receptors are the major inhibitory neurotransmitter receptors in the brain and are the site of action of many clinically important drugs. These receptors are composed of five subunits that can belong to eight different subunit classes. If all GABA(A) receptor subunits could randomly combine with each other, an extremely large number of GABA(A) receptor subtypes with distinct subunit composition and arrangement would be formed. Depending on their subunit composition, these receptors would exhibit distinct pharmacological and electrophysiological properties. Recent evidence, however, indicates that not all subunits can assemble efficiently with each other and form functional homo- or hetero-oligomeric receptors. In addition, the efficiency of formation of hetero-oligomeric assembly intermediates determines the subunit stoichiometry and subunit arrangement for each receptor and thus further reduces the possible heterogeneity of GABA(A) receptors in the brain. Studies investigating the subunit composition of native GABA(A) receptors support this conclusion, but also indicate that receptors composed of one, two, three, four, or five different subunits might exist in the brain. Using a recently established immunodepletion technique, the subunit composition and quantitative importance of native GABA(A) receptor subtypes can be determined. This information, together with studies on the regional, cellular and subcellular distribution of these receptor subtypes, will be the basis for a rational development of drugs that specifically affect the GABAergic system.

Animals↗
PubMed1999

Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakastani patients.

The dopamine D3 receptor (DRD3) appears to play an important role in the mediation of antipsychotic drug action. Genetic association of treatment response to the atypical antipsychotic drug clozapine with the DRD3 polymorphism Ser9Gly was investigated in a sample of 32 schizophrenic patients. We found association of treatment response with allele Gly-9 (P=0.0058) and with genotypes consisting of Gly-9 (P=0.033) by this pharmacogenetic approach. A combined analysis with two previous studies (Shaikh et al., Hum. Genet. 97 (1996) 714-719; Malhotra et al., Mol. Psychiatry 3 (1998) 72-75) further substantiates these results (P=0.0041).

Adult↗
PubMed1999

Serological cross-sectional study of paratuberculosis in cattle in Austria.

From 1995 to 1997, the prevalence of serum antibodies against Mycobacterium avium subspecies paratuberculosis (M. av. ssp. ptbc.)--the causal agent of paratuberculosis (Johne's Disease)--was examined in 11,028 Austrian cattle. Samples from the four oldest cattle on 2757 farms were collected according to a specific sampling schedule for this epidemiological study. District, age and breed of animals were included as variables in this study. For antibody screening against M. avium subspecies paratuberculosis, a modified, commercially available ELISA (ALLIED Monitors, Fayette, USA) was employed. A total of 2253 samples that were found to be positive or questionable were subjected to further testing with a more specific ELISA (Institute of Microbiology and Infectious Animal Diseases). Results of this study were used for statistical analysis. The average prevalence of antibodies to M. avium subspecies paratuberculosis was 1.99% in Austria. The highest prevalence was seen in 6-year-old cattle (2.84%) and Holstein Frisian cattle (3.51%). Sero-positive animals were found on 6.96% of farms tested, and the prevalence was highest in Vorarlberg, followed by Salzburg, the Tyrol, Styria and Carinthia. This study is unique in Europe in the use of an adequate random sampling plan for an investigation of this magnitude.

Age Factors↗
PubMed1999

Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the alpha6 subunit gene.

Any given subunit of the heteromultimeric type-A gamma-aminobutyric acid (GABA) GABAA receptor may be present in several receptor subtypes expressed by individual neurons. Changes in the expression of a subunit may result in differential changes in the expression of other subunits depending on the subunit composition of the receptor subtype, leading to alterations in neuronal responsiveness to GABA. We used the targeted disruption of the alpha6 subunit gene to test for changes in the expression of other GABAA receptor subunits. Immunoprecipitation and ligand binding experiments indicated that GABAA receptors were reduced by approximately 50% in the cerebellum of alpha6 -/- mice. Western blot experiments indicated that the alpha6 subunit protein completely disappeared from the cerebellum of alpha6 -/- mice, which resulted in the disappearance of the delta subunit from the plasma membrane of granule cells. The amount of beta2, beta3 and gamma2 subunits was reduced by approximately 50%, 20% and 40%, respectively, in the cerebella of alpha6 -/- mice. A comparison of the reduction in the level of alpha1, beta2, beta3, gamma2, or delta-subunit-containing receptors in alpha6 -/- cerebellum with those observed after removal of alpha6-subunit-containing receptors from the cerebella of alpha6 +/+ mice by immuno-affinity chromatography demonstrated the presence of a significantly higher than expected proportion of receptors containing beta3 subunits in alpha6 -/- mice. The receptors containing alpha1, beta2, beta3 and gamma2 subunits were present in the plasma membrane of granule cells of alpha6 -/- mice at both synaptic and extrasynaptic sites, as shown by electron microscopic immunocytochemistry. Despite the changes, the alpha1 subunit content of Golgi-cell-to-granule-cell synapses in alpha6 -/- animals remained unaltered, as did the frequency of alpha1 immunopositive synapses in the glomeruli. Furthermore, no change was apparent in the expression of the alpha1, beta2 and gamma2 subunits in Purkinje cells and interneurons of the molecular layer. These results demonstrate that in alpha6 -/- mice, the cerebellum expresses only half of the number of GABAA receptors present in wild-type animals. Since these animals have no gross motor deficits, synaptic integration in granule cells is apparently maintained by alpha1-subunit-containing receptors with an altered overall subunit composition, and/or by changes in the expression of other ligand and voltage gated channels.

Animals↗
PubMed1999

Glycaemic disorders in denture stomatitis.

The prevalence of glycaemic disorders was investigated in native Upper-Austrians with Candida-associated denture stomatitis. All patients with previously unknown diabetes mellitus were subjected to an oral glucose tolerance test (OGTT) and as a result diabetes was diagnosed in 13% of the patients over 50 years of age. Thirty-five percent of all inspected patients over 50 years of age with denture stomatitis had type 2 diabetes mellitus and 36% had impaired glucose tolerance (IGT). The correlation between Candida-associated denture stomatitis and diabetes mellitus indicates a means for the early diagnosis of diabetes. Hyperglycaemia could not be a predisposition to denture stomatitis, since all patients with denture stomatitis in the age-bracket 26-50 years were without diabetes and only very few of the older patients with diabetes were obese. The correlation between Candica-associated denture stomatitis and type 2 diabetes mellitus could be traced back to a reduced resistance to Candida that preceded the diabetes.

Adult↗
PubMed1998

Genetic polymorphisms for drug metabolism (CYP2D6) and tardive dyskinesia in schizophrenia.

In the present study, the occurrence of tardive dyskinesia (TD) in chronic schizophrenia patients was investigated in relation to pharmacogenetic polymorphisms. It is known that the metabolism of important neuroleptic drugs is influenced by polymorphisms of the CYP2D6 gene, which encodes the cytochrome P450 enzyme debrisoquine/spartein hydroxylase. Forty-five patients meeting the DSM IV criteria for schizophrenia, chronic course, were recruited. The patients were examined for the mutations CYP2D6*3, CYP2D6*4 and CYP2D6*5. The CYP2D6 genotype distribution in the patient group did not differ from that in healthy Caucasian populations. Tardive dyskinesia was found in 26 patients (57.8%). When comparing patients without CYP2D6 mutations with patients heterozygous for one mutation, we found a higher incidence of TD in the latter (81.3% vs. 46.4%, p = 0.031, multiple regression analysis), which demonstrates a significant influence of the CYP2D6 genotype of the manifestation of TD. As slight differences in the metabolism of drugs in patients heterozygous for CYP2D6 mutations and patients without such mutations are known, we conclude that heterozygous carriers of 2D6 mutated alleles may show an increased susceptibility to developing TD.

Adult↗
PubMed1998

European Multicentre Association Study of Schizophrenia: a study of the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms.

As part of the European Multicentre Association Study of Schizophrenia (EMASS), we studied polymorphisms in the dopamine DRD2 and DRD3 receptor genes. The EMASS collaboration was established to create a large, statistically powerful sample of schizophrenic patients and controls from different European centres. Previous studies have suggested associations between schizophrenia and the Ser311Cys polymorphism in exon 7 of the dopamine DRD2 receptor gene [Arinami et al., (1994): Lancet 343:703-704] and a polymorphism Ser9gly in exon 1 of the dopamine DRD3 receptor gene [Crocq et al. (1992): J Med Genet 29:858-860]. We tested for these associations in samples of 373 and 413, and 311 and 306 patients and controls, respectively. We found no evidence for allelic association between schizophrenia and the Cys311 variant of the DRD2 receptor gene and no homozygotes for this variant were observed by any group. However, an excess of homozygotes for both alleles of the DRD3 polymorphism was observed in schizophrenic patients (chi2 = 8.54, P = 0.003, odds ratio = 1.64, 95% CI = 1.18-2.29). We also observed a significant excess of the 1-1 (Ser9Ser) genotype (chi2 = 8.13, P = 0.004, odds ratio = 1.7, 95% CI = 1.18-2.4). No evidence of heterogeneity between samples was detected and there was no evidence of an allelic association. These findings suggest that the rare Cys311 variant in exon 7 of the DRD2 receptor gene does not play a role in the pathogenesis of schizophrenia in European populations. Currently, our results do support the previous findings of an association between increased homozygosity of the Ser/Gly variant of the Dopamine D3 receptor gene and schizophrenia.

Alleles↗
PubMed1997

No evidence for a schizophrenia susceptibility gene in the vicinity of IL2RB on chromosome 22.

Pulver et al. [1994a] reported modest linkage evidence for a dominantly (D) inherited "schizophrenia gene" in the vicinity of IL2RB on chromosome 22q12, and Coon et al. [1994] adduced moderate evidence under a recessive (R) model. We report here a replication study to test the hypothesis that one of these two models (or a third, intermediate (I) model) adequately describes the co-segregation of schizophrenia and chromosome 22q12 markers in an independent sample of 23 multiplex families. Altogether nine transmission models were evaluated. The models differed depending on whether the 15 family members with a diagnosis of schizophrenia spectrum disorders were considered unaffected (a "narrow" (N) definition), affected (a "wide" (W) definition), or declared "unknown" (U). The entire region between D22S268 and D22S307 is excluded (i.e., lod <-2) for models RN, RW, RU, and IW. Lod scores for the remaining models are uniformly negative; albeit, equivocal with respect to the dominant hypothesis over a small region between D22S268 and IL2RB. Nonparametric analysis under both diagnostic criteria also failed to yield any evidence for a susceptibility locus in this region of chromosome 22.

Chromosomes, Human, Pair 22↗
PubMed1997

Stoichiometry and assembly of a recombinant GABAA receptor subtype.

GABAA receptors are ligand-gated chloride ion channels that are presumed to be pentamers composed of alpha, beta, and gamma subunits. The subunit stoichiometry, however, is controversial, and the subunit arrangement presently is not known. In this study the ratio of subunits in recombinant alpha1beta3gamma2 receptors was determined in Western blots from the relative signal intensities of antibodies directed against the N terminus or the cytoplasmic loop of different subunits after the relative reactivity of these antibodies had been determined with GABAA receptor subunit chimeras composed of the N-terminal domain of one and the remaining part of the other subunit. Via this method a subunit stoichiometry of two alpha subunits, two beta subunits, and one gamma subunit was derived. Similar experiments investigating the composition of alpha1beta3 receptors expressed on the surface of human embryonic kidney (HEK) 293 cells cotransfected with alpha1 and beta3 subunits resulted in a stoichiometry of two alpha and three beta subunits. Density gradient centrifugation studies indicated that combinations of alpha1beta3gamma2 or alpha1beta3 subunits expressed in HEK 293 cells are able to form pentamers, whereas combinations of alpha1gamma2 or beta3gamma2 subunits predominantly form heterodimers. These results provide valuable information on the mechanism of GABAA receptor assembly and support the conclusion that GABAA receptors are pentamers in which a total of four alternating alpha and beta subunits are connected by a gamma subunit.

Base Sequence↗
PubMed1997

GABA(A) receptor subunits in the rat hippocampus II: altered distribution in kainic acid-induced temporal lobe epilepsy.

Intraperitoneal injection of kainic acid in the rat represents a widely used animal model of human temporal lobe epilepsy. Injection of kainic acid induces acute limbic seizures which are accompanied by seizure-induced brain damage and late spontaneous recurrent seizures. There is considerable evidence for an altered transmission of GABA in human temporal lobe epilepsy and in the kainic acid model. We therefore investigated by immunocytochemistry the distribution of 13 GABA receptor subunits in the hippocampus of rats 12 h, 24 h, and two, seven and 30 days after injection of kainic acid. Within the molecular layer of the dentate gyrus, decreases in alpha2- and delta- and slight increases in alpha1, beta2- and beta3-immunoreactivities were observed at early intervals (12 to 24 h) after kainic acid injection. These changes were succeeded by marked increases in alpha1-, alpha2-, alpha4-, alpha5-, beta1-, beta3-, gamma2- and delta-immunoreactivities in the same area after seven to 30 days. Within the hippocampus proper, changes in expression of GABA(A) receptor subunits were demarcated by considerable neurodegeneration of CA1 and CA3 pyramidal neurons. All subunits present within dendritic areas of CA1 and CA3 were affected. These were alpha1, alpha2, alpha5, beta1-beta3, gamma2 and alpha4 (present only in CA1). Decreases in these subunits were followed by increased expression of alpha2-, alpha5-, beta3-, gamma2- and delta-subunits in the hippocampus proper notably in CA3 at later intervals (up to 30 days). Alpha1-, beta2-, gamma2- and delta-subunits were found in presumed GABA containing interneurons throughout the hippocampus. Their immunoreactivity was augmented after two to seven days. Some alpha4-, gamma3- and delta-immunoreactivity was also found in astrocytes 48 h after kainic acid injection. Our data indicate an impairment of GABA-mediated neurotransmission due to a lasting loss of GABA(A) receptor containing cells after kainic acid-induced seizures. The seizure-induced loss in GABA(A) receptors within the hippocampus may in part be compensated by increased expression of GABA(A) receptor subunits within the molecular layer of the dentate gyrus and in pyramidal cells.

Animals↗
PubMed1997

GABA(A) receptor subunits in the rat hippocampus I: immunocytochemical distribution of 13 subunits.

The GABA(A) receptor is a ligand-operated chloride channel. It has a pentameric structure. In mammalian brain different subunits are recruited from four gene subfamilies. Using immunocytochemistry, we investigated the distribution of the 13 GABA(A) receptor subunits in the hippocampus of the rat. GABA(A) receptor subunits were heterogeneously distributed within different hippocampal subfields. High concentrations of alpha1-, alpha2-, alpha4-, beta3-, gamma2- and delta-immunoreactivities were observed within the molecular layer of the dentate gyrus, representing the dendritic area of the granule cells. In the hippocampus proper, the predominant GABA(A) receptor subunits were alpha1, alpha2, alpha5, beta3 and gamma2 that were located throughout the strata radiatum and oriens of CA1 to CA3. Immunocytochemical staining was there less prominent for alpha4-, beta1-, beta2- gamma3- and delta- subunits. In the hippocampus proper, the beta1 subunit was preferentially located in CA2. The alpha4- and delta-subunits were somewhat more abundant in CA1 than in CA3. Numerous local circuit neurons in the hippocampus proper and the hilus of the dentate gyrus contained alpha1-, beta2-, gamma2- and/or delta-subunits. Alpha3 and gamma1 were present only in minute amounts and no alpha6-IR was detected in the hippocampal formation. The distribution of the GABA(A) receptor subunits indicates the existence of heterogenously constituted GABA(A) receptor complexes within various hippocampal subfields, which may exert different physiological or pharmacological properties upon stimulation by GABA or its agonists.

Animals↗
PubMed1997

CYP2D6 genotype and phenotyping by determination of dextromethorphan and metabolites in serum of healthy controls and of patients under psychotropic medication.

Fourteen drug free healthy volunteers and 22 psychiatric patients under psychotropic medication were phenotyped for their individual CYP2D6 activity using dextromethorphan as a probe drug. A solution containing 20 mg dextromethorphan was administered and blood was taken 60 min later for determination of dextromethorphan and metabolites in serum. For comparison, urine was collected over 8 h after ingestion of 20 mg dextromethorphan in a separate test. The CYP2D6 phenotype was determined from the ratio of dextromethorphan to dextrorphan. For genotyping, mutant alleles of the CYP2D6 gene were identified using allele-specific polymerase chain reactions. Genotyping revealed five poor metabolizers of CYP2D6. The others were extensive metabolizers. The ratio of dextromethorphan to dextrorphan ranged from 0.01-2.53 in serum and from 0.0007-4.252 in urine. Probit analysis of serum ratios revealed a bimodal distribution with an antimode at 0.126. According to this antimode, control subjects exhibited identical phenotypes and genotypes, whereas patients under paroxetine, moclobemide or metoprolol who had been genotyped as extensive metabolizers were poor metabolizer phenotypes. Administration of tricyclic antidepressants did not change the CYP2D6 phenotype. The serum assay was more rapid and more accurate than the standard urine approach. Therefore the determination of dextromethorphan and metabolites in serum could be advantageous to measure individual CYP2D6 activities in vivo and thus optimize the dosing of drugs metabolized by CYP2D6.

Adult↗
PubMed1996

Effects of temporal lobe epilepsy on spatial and figural aspects of memory for a complex geometric figure.

The preoperative delayed memory performance on the Rey-Osterrieth Complex Figure (Lezak, 1983) of 54 patients with complex partial seizures of temporal lobe origin was analyzed using 3 different indices. One index (composite) was derived using a common scoring method that included both spatial and figural aspects of memory in its score. The other two indices were derived emphasizing either spatial or figural aspects of memory for the elements of the figure separately. All 3 indices distinguished between individuals with right-sided (RTLE) and left-sided (LTLE) seizure onset. However, spatial memory was significantly lower than figural memory in individuals with RTLE as compared to those with LTLE. Both the spatial and figural memory indices were significantly lower in the presence of magnetic resonance imaging (MRI) evidence for hippocampal sclerosis in individuals with RTLE. Results suggest that while both the spatial and figural aspects of nonverbal memory are sensitive to right hippocampal dysfunction, figural memory may be less vulnerable to the effects of RTLE.

Adult↗
PubMed1996

Schizophrenia and the dopamine-beta-hydroxylase gene: results of a linkage and association study.

Alterations in dopamine neurotransmission and disturbed norepinephrine activity have been implicated in the pathogenesis of schizophrenia. We considered the dopamine-beta-hydroxylase (DBH) gene located on the long arm of chromosome 9 (9q34.3) as a candidate gene for schizophrenia. DBH catalyzes the synthesis of norepinephrine from dopamine in noradrenergic neurons. In addition to DBH we used in the linkage study DNA markers ABL (centromeric) and D9S114 (telomeric). The aim of this study was to test linkage and association between PCR-based genotyped markers and schizophrenia. A simulation was done to investigate the power of our sample. In 34 Austrian families we could not detect linkage between schizophrenia and schizophrenia spectrum disorders and the three genetic markers. We could not find any significant deviation in allelic or genotypic distribution from expectations. Based on our results we conclude that the DBH gene seems to have no strong contribution in the etiology of schizophrenia.

Alleles↗
PubMed1996

Normal CAG repeats in the Huntington gene in a family with benign familial chorea.

Benign familial chorea (BFC) is a rare neurological disease with an autosomal dominant transmission. The disorder is characterized by its early onset in childhood, a non-progressive course of choreatic movements and the absence of intellectual impairment. There is one study describing an expanded (CAG)n repeat in the gene IT15 (Huntington) on chromosome 4p (causative for Huntington's chorea) in a family reported to have BFC that was diagnosed on the basis of onset and non-progressive course. We failed to find an expansion of the (CAG)n repeats in an Austrian family having BFC. The three affected individuals of the family had 18-25 CAG repeats. These results indicate that the diagnostic criteria for BFC should include a normal result in the analysis of the (CAG)n repeat region of the Huntington gene.

Adolescent↗
PubMed1995

Allosteric modulation of [3H]flunitrazepam binding to recombinant GABAA receptors.

The allosteric modulation of [3H]flunitrazepam binding by gamma-aminobutyric acid (GABA), pentobarbital, (+)-etomidate, etazolate, alphaxalone, propofol and chlormethiazole was investigated in cerebellar membranes and membranes from human embryonic kidney (HEK) 193 cells transfected with alpha 1 beta 3 gamma 2 or alpha 1 gamma 2 subunits. Results obtained indicate that [3H]flunitrazepam binding to recombinant GABAA receptors consisting of alpha 1 beta 3 gamma 2 subunits could be modulated by these compounds in a way and with a potency similar to that observed in cerebellar membranes. In addition, it was demonstrated that not only receptors consisting of alpha 1 beta 3 gamma 3, but also those consisting of alpha 1 gamma 2 subunits exhibited [3H]flunitrazepam binding which could be stimulated by GABA. In contrast to alpha 1 beta 3 gamma 2 receptors, however, [3H]flunitrazepam binding to recombinant alpha 1 gamma 2 receptors was inhibited by pentobarbital, (+)-etomidate, etazolate, alphaxalone, propofol and chlormethiazole. This seems to indicate that binding sites for these compounds are present on alpha 1 gamma 2 receptors, but that their allosteric interaction with [3H]flunitrazepam binding sites is different from that of alpha 1 beta 3 gamma 2 receptors.

Allosteric Regulation↗