TY - JOUR A1 - Wolf, Karen A1 - Braun, Attila A1 - Haining, Elizabeth J. A1 - Tseng, Yu-Lun A1 - Kraft, Peter A1 - Schuhmann, Michael K. A1 - Gotru, Sanjeev K. A1 - Chen, Wenchun A1 - Hermanns, Heike M. A1 - Stoll, Guido A1 - Lesch, Klaus-Peter A1 - Nieswandt, Bernhard T1 - Partially Defective Store Operated Calcium Entry and Hem(ITAM) Signaling in Platelets of Serotonin Transporter Deficient Mice JF - PLoS One N2 - Background Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation. Objective To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke. Results In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice. Conclusion Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization. KW - platelets KW - serotonin KW - integrins KW - blood flow KW - collagens KW - platelet activation KW - platelet aggregation KW - ischemic stroke Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146399 VL - 11 IS - 1 ER - TY - JOUR A1 - Spinelli, Simona A1 - Müller, Tanja A1 - Friedel, Miriam A1 - Sigrist, Hannes A1 - Lesch, Klaus-Peter A1 - Henkelman, Mark A1 - Rudin, Markus A1 - Seifritz, Erich A1 - Pryce, Christopher R. T1 - Effects of repeated adolescent stress and serotonin transporter gene partial knockout in mice on behaviors and brain structures relevant to major depression JF - Frontiers in Behavioral Neuroscience N2 - In humans, exposure to stress during development is associated with structural and functional alterations of the prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HC) and their circuits of connectivity, and with an increased risk for developing major depressive disorder particularly in carriers of the short (s) variant of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR). Although changes in these regions are found in carriers of the s allele and/or in depressed patients, evidence for a specific genotype x developmental stress effect on brain structure and function is limited. Here, we investigated the effect of repeated stress exposure during adolescence in mice with partial knockout of the 5-HIT gene (HET) vs. wildtype (WT) on early-adulthood behavioral measures and brain structure [using magnetic resonance imaging (MRI)] relevant to human major depression. Behaviorally, adolescent stress (AS) increased anxiety and decreased activity and did so to a similar degree in HET and WT. In a probabilistic reversal learning task, HET-AS mice achieved fewer reversals than did HET-No-AS mice. 5-HIT genotype and AS were without effect on corticosterone stress response. In terms of structural brain differences, AS reduced the volume of two long-range white matter tracts, the optic tract (OT) and the cerebral peduncle (CP), in WT mice specifically. In a region-of-interest analysis, AS was associated with increased HC volume and HET genotype with a decreased frontal lobe volume. In conclusion, we found that 5-HIT and AS genotype exerted long-term effects on behavior and development of brain regions relevant to human depression. KW - mouse-brain KW - white-matter integrity KW - linked polymorphic region KW - C57BL/6 mice KW - lerned helplessness KW - 5-HTTLPR polymorphism KW - childhood maltreatment KW - rhesus macaques KW - 3-dimensional MRI KW - life stress Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122240 VL - 7 ER - TY - JOUR A1 - Opitz, Timm A1 - Schuwerk, Tobias A1 - Paulus, Markus A1 - Kloo, Daniela A1 - Osterhaus, Christopher A1 - Lesch, Klaus‐Peter A1 - Sodian, Beate T1 - No links between genetic variation and developing theory of mind: A preregistered replication attempt of candidate gene studies JF - Developmental Science N2 - Genetic variability is being discussed as a source of inter‐individual differences in Theory of Mind development. Previous studies documented an association between variations in DRD4 VNTR 48 bp, OXTR rs53576, COMT rs4680, and Theory of Mind task performance. As empirical evidence on these associations is sparse, we conducted a preregistered replication attempt of a study reporting a link between DRD4 VNTR 48 bp and false belief understanding in 50‐month‐old children [Lackner, C., Sabbagh, M. A., Hallinan, E., Liu, X., & Holden, J. J. (2012). Developmental Science, 15(2), 272–280.]. Additionally, we attempted a replication of studies on the role of OXTR rs53576 and COMT rs4680 in Theory of Mind. In both replication attempts, we did not find any evidence for associations between the sampled genetic markers and Theory of Mind ability in a series of analyses. Extending the replication attempt of Lackner et al., we employed longitudinal data from several tasks and measurement points, which allowed us to run follow‐up robustness checks with more reliable scores. These extensive analyses corroborated our null finding. This comprehensive non‐replication is important to balance current research on genetic markers of Theory of Mind. In a combined evaluation of our own and previous studies, we point to substantial methodological issues that research on the genetic basis of Theory of Mind development faces. We conclude that these limitations currently prevent firm conclusions on genetic influences on Theory of Mind development. KW - COMT KW - DRD4 KW - false belief KW - OXTR KW - theory of mind Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238812 VL - 24 IS - 5 ER - TY - JOUR A1 - Strekalova, Tatyana A1 - Veniaminova, Ekaterina A1 - Svirin, Evgeniy A1 - Kopeikina, Ekaterina A1 - Veremeyko, Tatyana A1 - Yung, Amanda W. Y. A1 - Proshin, Andrey A1 - Tan, Shawn Zheng Kai A1 - Khairuddin, Sharafuddin A1 - Lim, Lee Wei A1 - Lesch, Klaus-Peter A1 - Walitza, Susanne A1 - Anthony, Daniel C. A1 - Ponomarev, Eugene D. T1 - Sex-specific ADHD-like behaviour, altered metabolic functions, and altered EEG activity in sialyltransferase ST3GAL5-deficient mice JF - Biomolecules N2 - A deficiency in GM3-derived gangliosides, resulting from a lack of lactosylceramide-alpha-2,3-sialyltransferase (ST3GAL5), leads to severe neuropathology, including epilepsy and metabolic abnormalities. Disruption of ganglioside production by this enzyme may also have a role in the development of neuropsychiatric disorders. ST3Gal5 knock-out (St3gal5\(^{−/−}\)) mice lack a-, b-, and c-series gangliosides, but exhibit no overt neuropathology, possibly owing to the production of compensatory 0-series glycosphingolipids. Here, we sought to investigate the possibility that St3gal5\(^{−/−}\) mice might exhibit attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In addition, we evaluated potential metabolic and electroencephalogram (EEG) abnormalities. St3gal5\(^{−/−}\) mice were subjected to behavioural testing, glucose tolerance tests, and the levels of expression of brain and peripheral A and B isoforms of the insulin receptor (IR) were measured. We found that St3gal5\(^{−/−}\) mice exhibit locomotor hyperactivity, impulsivity, neophobia, and anxiety-like behavior. The genotype also altered blood glucose levels and glucose tolerance. A sex bias was consistently found in relation to body mass and peripheral IR expression. Analysis of the EEG revealed an increase in amplitude in St3gal5\(^{−/−}\) mice. Together, St3gal5\(^{−/−}\) mice exhibit ADHD-like behaviours, altered metabolic and EEG measures providing a useful platform for better understanding of the contribution of brain gangliosides to ADHD and associated comorbidities. KW - lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5) KW - attention-deficit/hyperactivity disorder (ADHD) KW - insulin receptor (IR) KW - sex differences KW - electroencephalogram (EEG) KW - mice Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250071 SN - 2218-273X VL - 11 IS - 12 ER - TY - JOUR A1 - Svirin, Evgeniy A1 - Veniaminova, Ekaterina A1 - Costa-Nunes, João Pedro A1 - Gorlova, Anna A1 - Umriukhin, Aleksei A1 - Kalueff, Allan V. A1 - Proshin, Andrey A1 - Anthony, Daniel C. A1 - Nedorubov, Andrey A1 - Tse, Anna Chung Kwan A1 - Walitza, Susanne A1 - Lim, Lee Wei A1 - Lesch, Klaus-Peter A1 - Strekalova, Tatyana T1 - Predation stress causes excessive aggression in female mice with partial genetic inactivation of tryptophan hydroxylase-2: evidence for altered myelination-related processes JF - Cells N2 - The interaction between brain serotonin (5-HT) deficiency and environmental adversity may predispose females to excessive aggression. Specifically, complete inactivation of the gene encoding tryptophan hydroxylase-2 (Tph2) results in the absence of neuronal 5-HT synthesis and excessive aggressiveness in both male and female null mutant (Tph2\(^{−/−}\)) mice. In heterozygous male mice (Tph2\(^{+/−}\)), there is a moderate reduction in brain 5-HT levels, and when they are exposed to stress, they exhibit increased aggression. Here, we exposed female Tph2\(^{+/−}\) mice to a five-day rat predation stress paradigm and assessed their emotionality and social interaction/aggression-like behaviors. Tph2\(^{+/−}\) females exhibited excessive aggression and increased dominant behavior. Stressed mutants displayed altered gene expression of the 5-HT receptors Htr1a and Htr2a, glycogen synthase kinase-3 β (GSK-3β), and c-fos as well as myelination-related transcripts in the prefrontal cortex: myelin basic protein (Mbp), proteolipid protein 1 (Plp1), myelin-associated glycoprotein (Mag), and myelin oligodendrocyte glycoprotein (Mog). The expression of the plasticity markers synaptophysin (Syp) and cAMP response element binding protein (Creb), but not AMPA receptor subunit A2 (GluA2), were affected by genotype. Moreover, in a separate experiment, naïve female Tph2\(^{+/−}\) mice showed signs of enhanced stress resilience in the modified swim test with repeated swimming sessions. Taken together, the combination of a moderate reduction in brain 5-HT with environmental challenges results in behavioral changes in female mice that resemble the aggression-related behavior and resilience seen in stressed male mutants; additionally, the combination is comparable to the phenotype of null mutants lacking neuronal 5-HT. Changes in myelination-associated processes are suspected to underpin the molecular mechanisms leading to aggressive behavior. KW - tryptophan hydroxylase-2 (Tph2) KW - female aggression KW - 5-HT receptors KW - glycogen synthase kinase-3 β (GSK-3β) KW - myelination KW - predation stress Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267250 SN - 2073-4409 VL - 11 IS - 6 ER - TY - JOUR A1 - Grimm, Oliver A1 - Weber, Heike A1 - Kittel-Schneider, Sarah A1 - Kranz, Thorsten M. A1 - Jacob, Christian P. A1 - Lesch, Klaus-Peter A1 - Reif, Andreas T1 - Impulsivity and Venturesomeness in an Adult ADHD Sample: Relation to Personality, Comorbidity, and Polygenic Risk JF - Frontiers in Psychiatry N2 - While impulsivity is a basic feature of attention-deficit/hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive–neurotic type, an adventurous–hyperactive type with a stronger genetic component, and an anxious–inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background. KW - impulsivity KW - ADHD KW - polygenic risk score KW - venturesomeness KW - substance abuse disorder KW - attention KW - hyperactivity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219751 SN - 1664-0640 VL - 11 ER - TY - JOUR A1 - Cline, Brandon H. A1 - Costa-Nunes, Joao P. A1 - Cespuglio, Raymond A1 - Markova, Natalyia A1 - Santos, Ana I. A1 - Bukhman, Yury V. A1 - Kubatiev, Aslan A1 - Steinbusch, Harry W. M. A1 - Lesch, Klaus-Peter A1 - Strekalova, Tatyana T1 - Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression JF - Frontiers in Behavioral Neuroscience N2 - Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naive DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naive animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies. KW - phosphorylated glycogen synthase kinase-3beta (pGSK-3beta) KW - hippocampal plasticity KW - sleep EEG KW - aging KW - NMDA receptor subunits NR2A and NR2B KW - dicholine succinate KW - insulin receptor KW - chronic stress Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143992 VL - 9 IS - 37 ER - TY - JOUR A1 - Juhasz, Gabriella A1 - Gonda, Xenia A1 - Hullam, Gabor A1 - Eszlari, Nora A1 - Kovacs, David A1 - Lazary, Judit A1 - Pap, Dorottya A1 - Petschner, Peter A1 - Elliott, Rebecca A1 - Deakin, John Francis William A1 - Muir Anderson, Ian A1 - Antal, Peter A1 - Lesch, Klaus-Peter A1 - Bagdy, Gyorgy T1 - Variability in the effect of 5-HTTLPR on depression in a large European population: the role of age, symptom profile, type and intensity of life stressors JF - PLoS ONE N2 - Background Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity. Methods In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models. Results The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (\(\leq\)30) individuals. Limitations Our study is cross-sectional and applies self-report questionnaires. Conclusions Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups. KW - serotonin transporter gene KW - environment interaction KW - polymorphism KW - events KW - moderation KW - CB1 receptor antagonists KW - s allele KW - association KW - anxiety KW - metaanalysis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143703 VL - 10 IS - 3 ER - TY - JOUR A1 - Bodden, Carina A1 - Richter, S. Helene A1 - Schreiber, Rebecca S. A1 - Kloke, Vanessa A1 - Gerß, Joachim A1 - Palme, Rupert A1 - Lesch, Klaus-Peter A1 - Lewejohann, Lars A1 - Kaiser, Sylvia A1 - Sachser, Norbert T1 - Benefits of adversity?! How life history affects the behavioral profile of mice varying in serotonin transporter genotype JF - Frontiers in Behavioral Neuroscience N2 - Behavioral profiles are influenced by both positive and negative experiences as well as the genetic disposition. Traditionally, accumulating adversity over lifetime is considered to predict increased anxiety like behavior ("allostatic load"). The alternative "mismatch hypothesis" suggests increased levels of anxiety if the early environment differs from the later-life environment. Thus, there is a need for a whole-life history approach to gain a deeper understanding of how behavioral profiles are shaped. The aim of this study was to elucidate the effects of life history on the behavioral profile of mice varying in serotonin transporter (5-HIT) genotype, an established mouse model of increased anxiety-like behavior. For this purpose, mice grew up under either adverse or beneficial conditions during early phases of life. In adulthood, they were further subdivided so as to face a situation that either matched or mismatched the condition experienced so far, resulting in four different life histories. Subsequently, mice were tested for their anxiety-like and exploratory behavior. The main results were: (1) Life history profoundly modulated the behavioral profile. Surprisingly, mice that experienced early beneficial and later escapable adverse conditions showed less anxiety-like and more exploratory behavior compared to mice of other life histories. (2) Genotype significantly influenced the behavioral profile, with homozygous 5-HTT knockout mice displaying highest levels of anxiety-like and lowest levels of exploratory behavior. Our findings concerning life history indicate that the absence of adversity does not necessarily cause lower levels of anxiety than accumulating adversity. Rather, some adversity may be beneficial, particularly when following positive events. Altogether, we conclude that for an understanding of behavioral profiles, it is not sufficient to look at experiences during single phases of life, but the whole life history has to be considered. KW - anxiety-like behavior KW - maternal care KW - dangerous world KW - animal behavior KW - match-mismatch KW - chronic social stress KW - elevated plus-maze KW - 5-HTT KW - life history KW - predictive adaptive response hypothesis KW - developmental plasticity KW - knockout mice KW - environmental enrichment KW - allostatic load Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143723 VL - 9 IS - 47 ER - TY - JOUR A1 - Strekalova, Tatyana A1 - Pavlov, Dmitrii A1 - Trofimov, Alexander A1 - Anthony, Daniel C. A1 - Svistunov, Andrei A1 - Proshin, Andrey A1 - Umriukhin, Aleksei A1 - Lyundup, Alexei A1 - Lesch, Klaus-Peter A1 - Cespuglio, Raymond T1 - Hippocampal over-expression of cyclooxygenase-2 (COX-2) is associated with susceptibility to stress-induced anhedonia in mice JF - International Journal of Molecular Sciences N2 - The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram. KW - major depression KW - inducible cyclooxygenase-2 (COX-2) KW - hippocampus KW - anhedonia KW - chronic stress KW - stress resilience KW - fear conditioning KW - celecoxib KW - citalopram KW - mouse Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284056 SN - 1422-0067 VL - 23 IS - 4 ER -