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Biomedical subjects

K P Lesch

Publications and source records attributed to K P Lesch.

At least 19 recordsLinked to original sources
PubMed2007

No evidence for preferential transmission of common valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor gene (BDNF) in ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable common neurodevelopmental disorder with onset in childhood. A coding SNP (rs6265, Val66Met) of the brain-derived neurotrophic factor gene (BDNF) has recently been associated with ADHD. More specifically, paternal over-transmission of the common Val66 allele to affected children had been observed. We aimed to confirm these findings in a large, sufficiently powered, and well characterized German ADHD family sample. The Val66Met polymorphism of BDNF was genotyped in 294 families comprising one or more affected sibs (468 children). Contrary to previous reports, we did not observe over-transmission of the common Val66 allele, from either parent to affected children. We did not find support for an involvement of the Val66 allele of the Val66Met polymorphism of BDNF in the pathogenesis of ADHD in our sample.

Attention Deficit Disorder with Hyperactivity↗
PubMed2006

Altered neocortical cell density and layer thickness in serotonin transporter knockout mice: a quantitation study.

The neurotransmitter serotonin (5-HT) plays morphogenetic roles during development, and their alteration could contribute to autism pathogenesis in humans. To further characterize 5-HT's contributions to neocortical development, we assessed the thickness and neuronal cell density of various cerebral cortical areas in serotonin transporter (5-HTT) knockout (ko) mice, characterized by elevated extracellular 5-HT levels. The thickness of layer IV is decreased in 5-HTT ko mice compared with wild-type (wt) mice. The overall effect on cortical thickness, however, depends on the genetic background of the mice. Overall cortical thickness is decreased in many cortical areas of 5-HTT ko mice with a mixed c129-CD1-C57BL/6J background. Instead, 5-HTT ko mice backcrossed into the C57BL/6J background display increases in supragranular and infragranular layers, which compensate entirely for decreased layer IV thickness, resulting in unchanged or even enhanced cortical thickness. Moreover, significant increases in neuronal cell density are found in 5-HTT ko mice with a C57BL/6J background (wt:hz:ko ratio = 1.00:1.04:1.17) but not in the mixed c129-CD1-C57BL/6J 5-HTT ko animals. These results provide evidence of 5-HTT gene effects on neocortical morphology in epistatic interaction with genetic variants at other loci and may model the effect of functional 5-HTT gene variants on neocortical development in autism.

Animals↗
PubMed2006

Inactivation of 5HT transport in mice: modeling altered 5HT homeostasis implicated in emotional dysfunction, affective disorders, and somatic syndromes.

Animal models have not only become an essential tool for investigating the neurobiological function of genes that are involved in the etiopathogenesis of human behavioral and psychiatric disorders but are also fundamental in the development novel therapeutic strategies. As an example, inactivation of the serotonin (5HT) transporter (5Htt, Slc6a4) gene in mice expanded our view of adaptive 5HT uptake regulation and maintenance of 5HT homeostasis in the developing human brain and molecular processes underlying anxiety-related traits, as well as affective spectrum disorders including depression. 5Htt-deficient mice have been employed as a model complementary to direct studies of genetically complex traits and disorders, with important findings in biochemical, morphological, behavioral, and pharmacological areas. Based on growing evidence for a critical role of the 5HTT in the integration of synaptic connections in the rodent, nonhuman primate, and human brain during critical periods of development and adult life, more in-depth knowledge of the molecular mechanisms implicated in these fine-tuning processes is currently evolving. Moreover, demonstration of a joint influence of the 5HTT variation and environmental sources during early brain development advanced our understanding of the mechanism of genexgene and genexenvironment interactions in the developmental neurobiology of anxiety and depression. Lastly, imaging techniques, which become increasingly elaborate in displaying the genomic influence on brain system activation in response to environmental cues, have provided the means to bridge the gap between small effects of 5HTT variation and complex behavior, as well as psychopathological dimensions. The combination of elaborate genetic, epigenetic, imaging, and behavioral analyses will continue to generate new insight into 5HTT's role as a master control gene of emotion regulation.

Affective Symptoms↗
PubMed2006

Structural variation of the monoamine oxidase A gene promoter repeat polymorphism in nonhuman primates.

By conferring allele-specific transcriptional activity on the monoamine oxidase A (MAOA) gene in humans, length variation of a repetitive sequence [(variable number of tandem repeat (VNTR)] in the MAOA promoter influences a constellation of personality traits related to aggressive and antisocial behavior and increases the risk of neurodevelopmental and psychiatric disorders. Here, we have analyzed the presence and variability of this MAOA promoter repeat in several species of nonhuman primates. Sequence analysis of MAOA's transcriptional control region revealed the presence of the VNTR in chimpanzee (Pan troglodytes), bonobo (Pan paniscus), gorilla (Gorilla gorilla), orangutan (Pongo pygmaeus), rhesus macaque (Macaca mulatta) and Gelada baboon (Theropithecus gelada). The majority of P. troglodytes and P. paniscus showed a single repeat with a sequence identical to the VNTR sequence in humans. In contrast, analyses of the remaining species revealed shorter sequences similar to the first 18 bp of human VNTR. Compared with other nonhuman primates, the VNTR sequence of M. mulatta showed the highest length variability with allele frequencies of 35, 25 and 40% for the five, six and seven repeat variants, respectively. The extent of variability of the MAOA promoter repeat in both rhesus monkeys and humans supports the notion that there may be a relationship between functional MAOA expression and aggression-related traits in humans and rhesus macaque populations.

Animals↗
PubMed2005

No causative DLL4 mutations in periodic catatonia patients from 15q15 linked families.

Two well-supported theories of schizophrenia pathogenesis are the neurotransmitter theory and the neurodevelopmental theory, suggesting, respectively, that dysregulation of neurotransmitter signaling and abnormal brain development are causative in this disease. The strongest evidence of neurotransmitter involvement are suggestions of abnormal dopamine signaling in the prefrontal cortex and one of the strongest indications of developmental abnormalities contributing to this disease is an inverse layering of the prefrontal cortex. These two theories of schizophrenia pathogenesis can be united by their involvement of the prefrontal cortex, where structural abnormalities could lead to neurochemical abnormalities. Accordingly, any gene expressed in the prefrontal cortex of developing brains is a functional candidate for schizophrenia. We have previously reported strong linkage to 15q15 (LOD = 3. 57; P = 2.6 x 10(-5)) in a collection of German multiplex families segregating the periodic catatonia subtype of schizophrenia in a nearly Mendelian fashion. A gene within our 15q15 linkage region, DLL4, is expressed in developing forebrain and produces a NOTCH4 ligand. Variants of NOTCH4 are associated with schizophrenia, thus DLL4 is both a functional as well as a positional candidate for schizophrenia. We screened this gene for mutations in three affected individuals and two unrelated controls and found two previously unreported SNPs, one non-synonymous polymorphism that changed an arganine to a histadine in Exon 7 and one synonymous polymorphism in exons. The non-synonymous SNP is a rare variant in that it was not found in 100 control chromosomes; however, it did not cosegregate with the disease in the extended family so it is not causative in this pedigree. It is unlikely that mutations in DLL4 are causative in this collection of families with linkage to 15q15.

Adaptor Proteins, Signal Transducing↗
PubMed2005

A functional serotonin transporter gene polymorphism is associated with migraine with aura.

An association study was performed in 197 migraineurs with regard to a functional serotonin (5-HT) transporter (5-HTT) gene promoter polymorphism that leads to low or high 5-HT uptake activity. The frequency of the less active short allele was increased in migraineurs with aura but not in migraineurs without aura in comparison with the control population (p < 0.001). This indicates that the 5-HTT may be involved in the polygenic etiology of migraine with aura.

Alleles↗
PubMed2005

Genetic alterations of the murine serotonergic gene pathway: the neurodevelopmental basis of anxiety.

The relative contribution of genetic and environmental factors in the configuration of behavioral differences is among the most prolonged and contentious controversies in intellectual history. Although current views emphasize the joint influence of genes and environmental sources during early brain development, the physiological complexities of multiple gene-gene and gene-environment interactions in the developmental neurobiology of fear and anxiety remain elusive. Variation in genes coding for proteins that control serotonin (5-hydroxytryptamine, 5-HT) system development and plasticity, establish 5-HT neuron identity, and modulate 5-HT receptor-mediated signal transduction as well as cellular pathways have been implicated in the genetics of anxiety and related disorders. This review selects anxiety and avoidance as paradigmatic traits and behaviors, and it focuses on mouse models that have been modified by deletion of genes coding for key players of serotonergic neurotransmission. In particular, pertinent approaches regarding phenotypic changes in mice bearing inactivation mutations of 5-HT receptors, 5-HT transporter, and monoamine oxidase A and other genes related to 5-HT signaling will be discussed and major findings highlighted.

Animals↗
PubMed2005

Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation.

The tryptophan hydroxylase-2 gene (TPH2) codes for the enzyme of serotonin (5-HT) synthesis in the brain and variation of TPH2 has been implicated in disorders of emotion regulation. Here, we used functional magnetic resonance imaging (fMRI) to demonstrate that a potentially functional variant of TPH2 modulates amygdala responsiveness to emotional stimuli of both negative and positive valence.

Adolescent↗
PubMed2005

Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2's regulatory region (rs4570625, P=0.049; rs11178997, P=0.034), but not for the third SNP in intron 2 (rs4565946, P=0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P=0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes.

Adolescent↗
PubMed2005

Absence of reuptake of serotonin influences susceptibility to clinical autoimmune disease and neuroantigen-specific interferon-gamma production in mouse EAE.

Serotonin (5-hydroxytryptamine, 5-HT) is one of the most extensively studied neurotransmitters of the central nervous system. It also has been identified in constituents of the immune system. Therefore serotonin has been suggested to serve as a mediator of bidirectional interactions between the nervous system and the immune system. We investigated this interaction in experimental autoimmune encephalomyelitis (EAE), a well-defined animal model of autoimmune disease of the central nervous system (CNS) mimicking features of the human disease multiple sclerosis. EAE was induced by immunization with the autoantigens myelin basic protein (MBP) or the immunodominant peptide of myelin oligodendrocyte glycoprotein (MOG) spanning amino acids 35-55 (MOGp 35-55). We studied EAE in knockout (KO) mice lacking the 5-HT transporter (5-HTT) on a C57.BL/6 background, in comparison with wild-type C57.BL/6 animals. After immunization with MOGp 35-55, or with rat MBP, the disease courses of the 5-HTT knockout mice were attenuated as compared to wildtype control mice. This difference was more pronounced in female animals. To dissect potential immune mechanisms underlying this phenomenon, histological studies of the CNS and cytokine measurements in mononuclear cells from the spleens of 5-HTT KO mice and wild-type controls were performed. We found a reduction of the inflammatory infiltrate in the CNS and of the neuroantigen-specific production of IFN-gamma in splenocytes, again accompanied by a gender difference. These findings suggest a potential role of extracellular 5-HT homeostasis in the fine-tuning of neuroantigen-specific immune responses.

Acute Disease↗
PubMed2004

Association between allelic variation of serotonin transporter function and neuroticism in anxious cluster C personality disorders.

OBJECTIVE: Association between the low-activity variant of a polymorphism in the transcriptional control region of the serotonin transporter (5-HTTLPR) and neuroticism or harm avoidance was found in several but not all studies. The authors analyzed the influence of 5-HTTLPR variants on personality disorders. METHOD: Patients with personality disorders (N=320) and healthy volunteers (N=281) were studied with the Revised NEO Personality Inventory and the Tridimensional Personality Questionnaire. All were genotyped for 5-HTTLPR variants. RESULTS: No differences in 5-HTTLPR genotype distribution were detected between patients with cluster B and C personality disorders and comparison subjects. In contrast, among patients with a cluster C diagnosis, carriers of the low-activity short allele of the 5-HTTLPR exhibited higher neuroticism scores than noncarriers. CONCLUSIONS: These findings support the notion that there is no general association between the 5-HTTLPR and anxiety-related traits and that differential gene effects and/or gene-by-environment interactions are likely operative in distinct clinical subpopulations.

Adult↗
PubMed2003

Quantitation of 5HT3 receptors in forebrain of serotonin transporter deficient mice.

Mice deficient in the serotonin transporter (5HTT) display highly elevated extracellular 5HT levels. 5HT exerts ist effects via at least fourteen different cloned 5HT receptors located pre- and postsynaptically. In contrast to the other 5HT receptors, the 5HT3 receptor is a ionotropic receptor with ligand-gated cation channel function. Since G-protein-coupled 5HT receptors show extensive adaptive changes in 5HTT-deficient mice, we investigated whether 5HT3 receptors are also altered in these mice. Using quantitative autoradiography, we found that 5HT3 receptors are upregulated in frontal cortex (+46%), parietal cortex (+42%), and in stratum oriens of the CA3 region of the hippocampus (+18%) of 5HTT knockout mice. Changes in 5HT3 receptor mRNA expression, as determined by quantitative in situ hybridisation, were less pronounced. The adaptive changes of 5HT3 receptor expression constitute a part of the complex regulatory pattern of 5HT receptors in 5HTT knockout mice.

Animals↗
PubMed2003

Organic cation transporter capable of transporting serotonin is up-regulated in serotonin transporter-deficient mice.

The serotonin (5HT) transporter (5HTT) regulates serotonergic neurotransmission by mediating the reuptake of 5HT from the synaptic cleft. Although lacking the high affinity and selectivity of the 5HTT, the brain expresses a large number of other transporters, including the polyspecific organic cation transporters (OCTs). OCT1 and OCT3, members of the potential-sensitive organic cation transporter gene family, physiologically transport a wide spectrum of organic cations. In addition, both transporters mediate low-affinity 5HT transport and, therefore, may participate in the clearance of excessive 5HT. Because concentrations of extracellular 5HT are increased in the brain of 5HTT-deficient mice, they are a model for investigating the role of OCTs in 5HT system homeostasis. Here, we analyzed OCT1 and OCT3 gene expression in the brain of 5HTT knockout mice by semiquantitative competitive polymerase chain reaction and in situ hybridization. We demonstrate that, in 5HTT-deficient mice, OCT3 mRNA concentrations were significantly increased in the hippocampus, but not in other brain regions, including cortex, striatum, cerebellum, and brainstem. In contrast, no difference in OCT1 expression was detected between 5HTT knockout and control mice. Up-regulation of OCT3 expression and enhanced low-affinity 5HT uptake may limit the adverse effects of elevated extracellular 5HT and may play a critical role in maintaining 5HT-dependent functions of the hippocampus in the absence of 5HTT.

Animals↗
PubMed2003

Altered rapid eye movement sleep timing in serotonin transporter knockout mice.

The monoamine neurotransmitter serotonin has long been implicated in development and maintenance of sleep patterns, yet the role of the serotonin transporter (SERT) in these processes has not been evaluated in detail. We report that genetically engineered SERT knockout mice exhibit more REM sleep (REMS) than wild type littermates (11 vs 7% of recording time under baseline conditions) and display more frequent REMS bouts that last longer. This phenotype resembles the previously reported long-term effect of repeated treatment with SERT inhibitor compounds rather than the acute REMS suppressing effect of treatment with such compounds, and is thus likely to reflect neuroadaptations to the absence of SERT, rather than an acute effect of its absence in the adult. While electroencephalographic (EEG) spectra did not differ between SERT knockout and wild type mice during non-REM sleep (NREMS) or REMS, the dynamics of the EEG during the transition from NREMS to REMS differed between the genotypes. The surge in EEG power in both the 6-9 Hz and 10-16 Hz ranges that occurs just prior to the onset of REMS (pre-REMS power surge) is of greater magnitude in SERT knockout mice than in wild type littermate controls. This observation contrasts with the reduced magnitude pre-REMS power surge observed in rats subjected to REMS deprivation relative to yoked controls. These results indicate that the pre-REMS power surge is influenced by REMS history and by monoaminergic transmission. Genetic differences in serotonin systems and developmental exposure to SERT blockers are likely to exert effects on REMS.

Animals↗
PubMed2003

Glucocorticoid-regulated human serotonin transporter (5-HTT) expression is modulated by the 5-HTT gene-promotor-linked polymorphic region.

Mood, emotion and cognition are modulated by serotonergic neurotransmission, while the physiological function of serotonergic synapses depends on serotonin reuptake, which is mediated by the serotonin transporter (5-HTT). Allelic variation of 5-HTT expression in humans is caused by a functional gene-promoter polymorphism with two predominant variant alleles, which are associated with variations in anxiety measures as previously reported. Here we report that administration of dexamethasone, a potent glucocorticosteroid hormone, results in an increase in 5-HTT expression in immortalized human B-lymphoblastoid cells, which express the human 5-HTT. Functional reporter gene assays as well as 5-HT uptake and inhibitor binding measures revealed a genotype-dependent dose-response to glucocorticosteroid administration, which was antagonized by RU 38486, a non-specific glucocorticosteroid hormone antagonist. The allele-specific differences after administration of dexamethasone depended on the repetitive GC-rich sequence located approximately 1.4 kb upstream of the 5-HTT gene transcription site because of absence of a significant steroid effect after transfecting a deletional mutant reporter gene construct, which lacks this repetitive promoter sequence. Our findings may contribute to explain the vulnerability to stress-related disorders in susceptible individuals, in whom further clinical studies should follow up on these in vitro findings.

B-Lymphocytes↗
PubMed2003

Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders.

Current evidence indicates that virtually all neuropsychiatric disorders, like many other common medical disorders, are genetically complex, with combined influences from multiple interacting genes, as well as from the environment. However, additive or epistatic gene interactions have proved quite difficult to detect and evaluate in human studies. Mouse phenotypes, including behaviors and drug responses, can provide relevant models for human disorders. Studies of gene-gene interactions in mice could thus help efforts to understand the molecular genetic bases of complex human disorders. The serotonin transporter (SERT, 5-HTT, SLC6A4) provides a relevant model for studying such interactions for several reasons: human variants in SERT have been associated with several neuropsychiatric and other medical disorders and quantitative traits; SERT blockers are effective treatments for a number of neuropsychiatric disorders; there is a good initial understanding of the phenotypic features of heterozygous and homozygous SERT knockout mice; and there is an expanding understanding of the interactions between variations in SERT expression and variations in the expression of a number of other genes of interest for neuropsychiatry and neuropharmacology. This paper provides examples of experimentally-obtained interactions between quantitative variations in SERT gene expression and variations in the expression of five other mouse genes: DAT, NET, MAOA, 5-HT(1B) and BDNF. In humans, all six of these genes possess polymorphisms that have been independently investigated as candidates for neuropsychiatric and other disorders in a total of > 500 reports. In the experimental studies in mice reviewed here, gene-gene interactions resulted in either synergistic, antagonistic (including 'rescue' or 'complementation') or more complex, quantitative alterations. These were identified in comparisons of the behavioral, physiological and neurochemical phenotypes of wildtype mice vs. mice with single allele or single gene targeted disruptions and mice with partial or complete disruptions of multiple genes. Several of the descriptive phenotypes could be best understood on the basis of intermediate, quantitative alterations such as brain serotonin differences. We discuss the ways in which these interactions could provide models for studies of gene-gene interactions in complex human neuropsychiatric and other disorders to which SERT may contribute, including developmental disorders, obesity, polysubstance abuse and others.

Animals↗