TY - JOUR A1 - Zayats, T A1 - Jacobsen, KK A1 - Kleppe, R A1 - Jacob, CP A1 - Kittel-Schneider, S A1 - Ribasés, M A1 - Ramos-Quiroga, JA A1 - Richarte, V A1 - Casas, M A1 - Mota, NR A1 - Grevet, EH A1 - Klein, M A1 - Corominas, J A1 - Bralten, J A1 - Galesloot, T A1 - Vasquez, AA A1 - Herms, S A1 - Forstner, AJ A1 - Larsson, H A1 - Breen, G A1 - Asherson, P A1 - Gross-Lesch, S A1 - Lesch, KP A1 - Cichon, S A1 - Gabrielsen, MB A1 - Holmen, OL A1 - Bau, CHD A1 - Buitelaar, J A1 - Kiemeney, L A1 - Faraone, SV A1 - Cormand, B A1 - Franke, B A1 - Reif, A A1 - Haavik, J A1 - Johansson, S T1 - Exome chip analyses in adult attention deficit hyperactivity disorder JF - Translational Psychiatry N2 - Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E−06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E−08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E−07); the PSD locus (P=7.58E−08) and ZCCHC4 locus (P=1.79E−06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E−05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD. KW - chip analyses KW - ADHD KW - adulthood KW - Illumina Human Exome Bead Chip Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168297 VL - 6 IS - e923 ER - TY - JOUR A1 - Strekalova, Tatyana A1 - Markova, Nataliia A1 - Shevtsova, Elena A1 - Zubareva, Olga A1 - Bakhmet, Anastassia A1 - Steinbusch, Harry M. A1 - Bachurin, Sergey A1 - Lesch, Klaus-Peter T1 - Individual Differences in Behavioural Despair Predict Brain GSK-3beta Expression in Mice: The Power of a Modified Swim Test JF - Neural Plasticity N2 - While deficient brain plasticity is a well-established pathophysiologic feature of depression, little is known about disorder-associated enhanced cognitive processing. Here, we studied a novel mouse paradigm that potentially models augmented learning of adverse memories during development of a depressive-like state. We used a modification of the classic two-day protocol of a mouse Porsolt test with an additional session occurring on Day 5 following the initial exposure. Unexpectedly, floating behaviour and brain glycogen synthase kinase-3 beta (GSK-3beta) mRNA levels, a factor of synaptic plasticity as well as a marker of distress and depression, were increased during the additional swimming session that was prevented by imipramine. Observed increases of GSK-3beta mRNA in prefrontal cortex during delayed testing session correlated with individual parameters of behavioural despair that was not found in the classic Porsolt test. Repeated swim exposure was accompanied by a lower pGSK-3beta/GSK-3beta ratio. A replacement of the second or the final swim sessions with exposure to the context of testing resulted in increased GSK-3beta mRNA level similar to the effects of swimming, while exclusion of the second testing prevented these changes. Together, our findings implicate the activation of brain GSK-3beta expression in enhanced contextual conditioning of adverse memories, which is associated with an individual susceptibility to a depressive syndrome. KW - mice KW - swim test Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147379 VL - 2016 ER - TY - JOUR A1 - Neufang, S. A1 - Akhrif, A. A1 - Herrmann, C.G. A1 - Drepper, C. A1 - Homola, G.A. A1 - Nowak, J. A1 - Waider, J. A1 - Schmitt, A.G. A1 - Lesch, K.-P. A1 - Romanos, M. T1 - Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans JF - Translational Psychiatry N2 - In rodents, the five-choice serial reaction time task (5-CSRTT) has been established as a reliable measure of waiting impulsivity being defined as the ability to regulate a response in anticipation of reinforcement. Key brain structures are the nucleus accumbens (NAcc) and prefrontal regions (for example, pre- and infralimbic cortex), which are, together with other transmitters, modulated by serotonin. In this functional magnetic resonance imaging study, we examined 103 healthy males while performing the 5-CSRTT measuring brain activation in humans by means of a paradigm that has been widely applied in rodents. Subjects were genotyped for the tryptophan hydroxylase-2 (TPH2; G-703T; rs4570625) variant, an enzyme specific for brain serotonin synthesis. We addressed neural activation patterns of waiting impulsivity and the interaction between the NAcc and the ventromedial prefrontal cortex (vmPFC) using dynamic causal modeling. Genetic influence was examined via interaction analyses between the TPH2 genotype (GG homozygotes vs T allele carriers) and the degree of impulsivity as measured by the 5-CSRTT. We found that the driving input of the vmPFC was reduced in highly impulsive T allele carriers (reflecting a reduced top-down control) in combination with an enhanced response in the NAcc after correct target processing (reflecting an augmented response to monetary reward). Taken together, we found a high overlap of our findings with reports from animal studies in regard to the underlying cognitive processes, the brain regions associated with waiting impulsivity and the neural interplay between the NAcc and vmPFC. Therefore, we conclude that the 5-CSRTT is a promising tool for translational studies. KW - Clinical Genetics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164418 IS - 6 ER - TY - JOUR A1 - Meyer, Neele A1 - Richter, S. Helene A1 - Schreiber, Rebecca S. A1 - Kloke, Vanessa A1 - Kaiser, Sylvia A1 - Lesch, Klaus-Peter A1 - Sachser, Norbert T1 - The Unexpected Effects of Beneficial and Adverse Social Experiences during Adolescence on Anxiety and Aggression and Their Modulation by Genotype JF - Frontiers in Behavioral Neuroscience N2 - Anxiety and aggression are part of the behavioral repertoire of humans and animals. However, in their exaggerated form both can become maladaptive and result in psychiatric disorders. On the one hand, genetic predisposition has been shown to play a crucial modulatory role in anxiety and aggression. On the other hand, social experiences have been implicated in the modulation of these traits. However, so far, mainly experiences in early life phases have been considered crucial for shaping anxiety-like and aggressive behavior, while the phase of adolescence has largely been neglected. Therefore, the aim of the present study was to elucidate how levels of anxiety-like and aggressive behavior are shaped by social experiences during adolescence and serotonin transporter (5-HTT) genotype. For this purpose, male mice of a 5-HTT knockout mouse model including all three genotypes (wildtype, heterozygous and homozygous 5-HTT knockout mice) were either exposed to an adverse social situation or a beneficial social environment during adolescence. This was accomplished in a custom-made cage system where mice experiencing the adverse environment were repeatedly introduced to the territory of a dominant opponent but had the possibility to escape to a refuge cage. Mice encountering beneficial social conditions had free access to a female mating partner. Afterwards, anxiety-like and aggressive behavior was assessed in a battery of tests. Surprisingly, unfavorable conditions during adolescence led to a decrease in anxiety-like behavior and an increase in exploratory locomotion. Additionally, aggressive behavior was augmented in animals that experienced social adversity. Concerning genotype, homozygous 5-HTT knockout mice were more anxious and less aggressive than heterozygous 5-HTT knockout and wildtype mice. In summary, adolescence is clearly an important phase in which anxiety-like and aggressive behavior can be shaped. Furthermore, it seems that having to cope with challenge during adolescence instead of experiencing throughout beneficial social conditions leads to reduced levels of anxiety-like behavior. KW - adolescence KW - aggressiveness KW - serotonin transporter KW - coping with challenge KW - adversity KW - anxiety-like behavior KW - social experience KW - 5-HTT knockout mice Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165090 VL - 10 IS - 97 ER - TY - JOUR A1 - Ip, Chi Wang A1 - Isaias, Ioannis U. A1 - Kusche-Tekin, Burak B. A1 - Klein, Dennis A1 - Groh, Janos A1 - O´Leary, Aet A1 - Knorr, Susanne A1 - Higuchi, Takahiro A1 - Koprich, James B. A1 - Brotchie, Jonathan M. A1 - Toyka, Klaus V. A1 - Reif, Andreas A1 - Volkmann, Jens T1 - Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury JF - Acta Neuropathologica Communications N2 - Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 % (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia. KW - Dystonia KW - DYT1 KW - dopamine KW - peripheral injury KW - second hit Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147839 VL - 4 IS - 108 ER - TY - JOUR A1 - Couch, Yvonne A1 - Trofimov, Alexander A1 - Markova, Natalyia A1 - Nikolenko, Vladimir A1 - Steinbusch, Harry W. A1 - Chekhonin, Vladimir A1 - Schroeter, Careen A1 - Lesch, Klaus-Peter A1 - Anthony, Daniel C. A1 - Strekalova, Tatyana T1 - Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice JF - Journal of Neuroinflammation N2 - Background Aggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. However, chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. Here, we examined whether stress-induced behavioural and molecular responses are analogous to lipopolysaccharide (LPS)-induced behavioural and molecular effects and whether their combination is adaptive or maladaptive. Methods Changes in measures of hedonic sensitivity, helplessness, aggression, impulsivity and CNS and systemic cytokine and 5-HT-system-related gene expression were investigated in C57BL/6J male mice exposed to chronic stress alone, low-dose LPS alone or a combination of LPS and stress. Results When combined with a low dose of LPS, chronic stress resulted in an enhanced depressive-like phenotype but significantly reduced manifestations of aggression and hyperactivity. At the molecular level, LPS was a strong inducer of TNFα, IL-1β and region-specific 5-HT2A mRNA expression in the brain. There was also increased serum corticosterone as well as increased TNFα expression in the liver. Stress did not induce comparable levels of cytokine expression to an LPS challenge, but the combination of stress with LPS reduced the stress-induced changes in 5-HT genes and the LPS-induced elevated IL-1β levels. Conclusions It is evident that when administered independently, both stress and LPS challenges induced distinct molecular and behavioural changes. However, at a time when LPS alone does not induce any overt behavioural changes per se, the combination with stress exacerbates depressive and inhibits aggressive behaviours. KW - SERT KW - Chronic stress KW - LPS KW - Aggressive behaviour KW - S-HT KW - Cytokines Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165676 VL - 13 IS - 108 ER - TY - JOUR A1 - Brevik, Erlend J A1 - van Donkelaar, Marjolein M. J. A1 - Weber, Heike A1 - Sánchez-Mora, Cristina A1 - Jacob, Christian A1 - Rivero, Olga A1 - Kittel-Schneider, Sarah A1 - Garcia-martinez, Iris A1 - Aebi, Marcel A1 - van Hulzen, Kimm A1 - Cormand, Bru A1 - Ramos-Quiroga, Josep A A1 - Lesch, Klaus-Peter A1 - Reif, Andreas A1 - Ribases, Marta A1 - Franke, Barbara A1 - Posserud, Maj-Britt A1 - Johansson, Stefan A1 - Lundervold, Astri J. A1 - Haavik, Jan A1 - Zayats, Tetyana T1 - Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder JF - American Journal of Medical Genetics Part B-Neuropsychiatric Genetics N2 - Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P<5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. KW - Large multicenter ADHD KW - Antisocial behavior KW - Diagnostic approach KW - Rating scale KW - Gene KW - Deficit/hyperactivity disorder KW - Susceptibility loci KW - Conduct disorder KW - Association KW - Adult KW - ADHD KW - Aggression KW - GWAS Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188116 VL - 171B IS - 5 ER -