@article{JuhaszGondaHullametal.2015, author = {Juhasz, Gabriella and Gonda, Xenia and Hullam, Gabor and Eszlari, Nora and Kovacs, David and Lazary, Judit and Pap, Dorottya and Petschner, Peter and Elliott, Rebecca and Deakin, John Francis William and Muir Anderson, Ian and Antal, Peter and Lesch, Klaus-Peter and Bagdy, Gyorgy}, title = {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}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0116316}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143703}, pages = {e0116316}, year = {2015}, abstract = {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.}, language = {en} } @article{GorlovaSvirinPavlovetal.2023, author = {Gorlova, Anna and Svirin, Evgeniy and Pavlov, Dmitrii and Cespuglio, Raymond and Proshin, Andrey and Schroeter, Careen A. and Lesch, Klaus-Peter and Strekalova, Tatyana}, title = {Understanding the role of oxidative stress, neuroinflammation and abnormal myelination in excessive aggression associated with depression: recent input from mechanistic studies}, series = {International Journal of Molecular Sciences}, volume = {24}, journal = {International Journal of Molecular Sciences}, number = {2}, issn = {1422-0067}, doi = {10.3390/ijms24020915}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304917}, year = {2023}, abstract = {Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless, the aetiology and pathophysiology of MDD has been the subject of extensive research and there is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify these processes, as many of these pathways are integrated for the neurobiology of MDD. We also describe the current translational approaches in modelling depression, including the recent advances in stress models of MDD, and emerging novel therapies, including novel approaches to management of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions.}, language = {en} } @article{LechermeierZimmerLueffeetal.2019, author = {Lechermeier, Carina G. and Zimmer, Frederic and L{\"u}ffe, Teresa M. and Lesch, Klaus-Peter and Romanos, Marcel and Lillesaar, Christina and Drepper, Carsten}, title = {Transcript analysis of zebrafish GLUT3 genes, slc2a3a and slc2a3b, define overlapping as well as distinct expression domains in the zebrafish (Danio rerio) central nervous system}, series = {Frontiers in Molecular Neuroscience}, volume = {12}, journal = {Frontiers in Molecular Neuroscience}, number = {199}, doi = {10.3389/fnmol.2019.00199}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201797}, year = {2019}, abstract = {The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo. GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington's and Alzheimer's diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish (Danio rerio) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b. Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a. Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders.}, language = {en} } @article{MeyerRichterSchreiberetal.2016, author = {Meyer, Neele and Richter, S. Helene and Schreiber, Rebecca S. and Kloke, Vanessa and Kaiser, Sylvia and Lesch, Klaus-Peter and Sachser, Norbert}, title = {The Unexpected Effects of Beneficial and Adverse Social Experiences during Adolescence on Anxiety and Aggression and Their Modulation by Genotype}, series = {Frontiers in Behavioral Neuroscience}, volume = {10}, journal = {Frontiers in Behavioral Neuroscience}, number = {97}, doi = {10.3389/fnbeh.2016.00097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165090}, year = {2016}, abstract = {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.}, language = {en} } @article{SchartlWalterShenetal.2013, author = {Schartl, Manfred and Walter, Ronald B. and Shen, Yingjia and Garcia, Tzintzuni and Catchen, Julian and Amores, Angel and Braasch, Ingo and Chalopin, Domitille and Volff, Jean-Nicolas and Lesch, Klaus-Peter and Bisazza, Angelo and Minx, Pat and Hillier, LaDeana and Wilson, Richard K. and F{\"u}rstenberg, Susan and Boore, Jeffrey and Searle, Steve and Postlethwait, John H. and Warren, Wesley C.}, title = {The genome of the platyfish, Xiphophorus maculatus, provides insights into evolutionary adaptation and several complex traits}, series = {Nature Genetics}, volume = {45}, journal = {Nature Genetics}, number = {5}, doi = {10.1038/ng.2604}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132152}, pages = {567-572}, year = {2013}, abstract = {Several attributes intuitively considered to be typical mammalian features, such as complex behavior, live birth and malignant disease such as cancer, also appeared several times independently in lower vertebrates. The genetic mechanisms underlying the evolution of these elaborate traits are poorly understood. The platyfish, X. maculatus, offers a unique model to better understand the molecular biology of such traits. We report here the sequencing of the platyfish genome. Integrating genome assembly with extensive genetic maps identified an unexpected evolutionary stability of chromosomes in fish, in contrast to in mammals. Genes associated with viviparity show signatures of positive selection, identifying new putative functional domains and rare cases of parallel evolution. We also find that genes implicated in cognition show an unexpectedly high rate of duplicate gene retention after the teleost genome duplication event, suggesting a hypothesis for the evolution of the behavioral complexity in fish, which exceeds that found in amphibians and reptiles.}, language = {en} } @article{StrekalovaVeniaminovaSvirinetal.2021, author = {Strekalova, Tatyana and Veniaminova, Ekaterina and Svirin, Evgeniy and Kopeikina, Ekaterina and Veremeyko, Tatyana and Yung, Amanda W. Y. and Proshin, Andrey and Tan, Shawn Zheng Kai and Khairuddin, Sharafuddin and Lim, Lee Wei and Lesch, Klaus-Peter and Walitza, Susanne and Anthony, Daniel C. and Ponomarev, Eugene D.}, title = {Sex-specific ADHD-like behaviour, altered metabolic functions, and altered EEG activity in sialyltransferase ST3GAL5-deficient mice}, series = {Biomolecules}, volume = {11}, journal = {Biomolecules}, number = {12}, issn = {2218-273X}, doi = {10.3390/biom11121759}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250071}, year = {2021}, abstract = {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.}, language = {en} } @article{JanschZieglerForeroetal.2021, author = {Jansch, Charline and Ziegler, Georg C. and Forero, Andrea and Gredy, Sina and W{\"a}ldchen, Sina and Vitale, Maria Rosaria and Svirin, Evgeniy and Z{\"o}ller, Johanna E. M. and Waider, Jonas and G{\"u}nther, Katharina and Edenhofer, Frank and Sauer, Markus and Wischmeyer, Erhard and Lesch, Klaus-Peter}, title = {Serotonin-specific neurons differentiated from human iPSCs form distinct subtypes with synaptic protein assembly}, series = {Journal of Neural Transmission}, volume = {128}, journal = {Journal of Neural Transmission}, number = {2}, issn = {1435-1463}, doi = {10.1007/s00702-021-02303-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-268519}, pages = {225-241}, year = {2021}, abstract = {Human induced pluripotent stem cells (hiPSCs) have revolutionized the generation of experimental disease models, but the development of protocols for the differentiation of functionally active neuronal subtypes with defined specification is still in its infancy. While dysfunction of the brain serotonin (5-HT) system has been implicated in the etiology of various neuropsychiatric disorders, investigation of functional human 5-HT specific neurons in vitro has been restricted by technical limitations. We describe an efficient generation of functionally active neurons from hiPSCs displaying 5-HT specification by modification of a previously reported protocol. Furthermore, 5-HT specific neurons were characterized using high-end fluorescence imaging including super-resolution microscopy in combination with electrophysiological techniques. Differentiated hiPSCs synthesize 5-HT, express specific markers, such as tryptophan hydroxylase 2 and 5-HT transporter, and exhibit an electrophysiological signature characteristic of serotonergic neurons, with spontaneous rhythmic activities, broad action potentials and large afterhyperpolarization potentials. 5-HT specific neurons form synapses reflected by the expression of pre- and postsynaptic proteins, such as Bassoon and Homer. The distribution pattern of Bassoon, a marker of the active zone along the soma and extensions of neurons, indicates functionality via volume transmission. Among the high percentage of 5-HT specific neurons (~ 42\%), a subpopulation of CDH13 + cells presumably designates dorsal raphe neurons. hiPSC-derived 5-HT specific neuronal cell cultures reflect the heterogeneous nature of dorsal and median raphe nuclei and may facilitate examining the association of serotonergic neuron subpopulations with neuropsychiatric disorders.}, language = {en} } @article{WaiderPoppMlinaretal.2019, author = {Waider, Jonas and Popp, Sandy and Mlinar, Boris and Montalbano, Alberto and Bonfiglio, Francesco and Aboagye, Benjamin and Thuy, Elisabeth and Kern, Raphael and Thiel, Christopher and Araragi, Naozumi and Svirin, Evgeniy and Schmitt-B{\"o}hrer, Angelika G. and Corradetti, Renato and Lowry, Christopher A. and Lesch, Klaus-Peter}, title = {Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity}, series = {Frontiers in Neuroscience}, volume = {13}, journal = {Frontiers in Neuroscience}, number = {245}, issn = {1662-453X}, doi = {10.3389/fnins.2019.00245}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196077}, year = {2019}, abstract = {Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.}, language = {en} } @article{SongJiaZhangetal.2016, author = {Song, Ning-Ning and Jia, Yun-Fang and Zhang, Lei and Zhang, Qiong and Huang, Ying and Liu, Xiao-Zhen and Hu, Ling and Lan, Wei and Chen, Ling and Lesch, Klaus-Peter and Chen, Xiaoyan and Xu, Lin and Ding, Yu-Qiang}, title = {Reducing central serotonin in adulthood promotes hippocampal neurogenesis}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, number = {20338}, doi = {10.1038/srep20338}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-168004}, year = {2016}, abstract = {Chronic administration of selective serotonin reuptake inhibitors (SSRIs), which up-regulates central serotonin (5-HT) system function, enhances adult hippocampal neurogenesis. However, the relationship between central 5-HT system and adult neurogenesis has not fully been understood. Here, we report that lowering 5-HT level in adulthood is also able to enhance adult hippocampal neurogenesis. We used tamoxifen (TM)-induced Cre in Pet1-CreER\(^{T2}\) mice to either deplete central serotonergic (5-HTergic) neurons or inactivate 5-HT synthesis in adulthood and explore the role of central 5-HT in adult hippocampal neurogenesis. A dramatic increase in hippocampal neurogenesis is present in these two central 5-HT-deficient mice and it is largely prevented by administration of agonist for 5-HTR2c receptor. In addition, the survival of new-born neurons in the hippocampus is enhanced. Furthermore, the adult 5-HT-deficient mice showed reduced depression-like behaviors but enhanced contextual fear memory. These findings demonstrate that lowering central 5-HT function in adulthood can also enhance adult hippocampal neurogenesis, thus revealing a new aspect of central 5-HT in regulating adult neurogenesis.}, language = {en} } @article{SvirinVeniaminovaCostaNunesetal.2022, author = {Svirin, Evgeniy and Veniaminova, Ekaterina and Costa-Nunes, Jo{\~a}o Pedro and Gorlova, Anna and Umriukhin, Aleksei and Kalueff, Allan V. and Proshin, Andrey and Anthony, Daniel C. and Nedorubov, Andrey and Tse, Anna Chung Kwan and Walitza, Susanne and Lim, Lee Wei and Lesch, Klaus-Peter and Strekalova, Tatyana}, title = {Predation stress causes excessive aggression in female mice with partial genetic inactivation of tryptophan hydroxylase-2: evidence for altered myelination-related processes}, series = {Cells}, volume = {11}, journal = {Cells}, number = {6}, issn = {2073-4409}, doi = {10.3390/cells11061036}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267250}, year = {2022}, abstract = {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, na{\"i}ve 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.}, language = {en} }