@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{StrekalovaPavlovTrofimovetal.2022, author = {Strekalova, Tatyana and Pavlov, Dmitrii and Trofimov, Alexander and Anthony, Daniel C. and Svistunov, Andrei and Proshin, Andrey and Umriukhin, Aleksei and Lyundup, Alexei and Lesch, Klaus-Peter and Cespuglio, Raymond}, title = {Hippocampal over-expression of cyclooxygenase-2 (COX-2) is associated with susceptibility to stress-induced anhedonia in mice}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {4}, issn = {1422-0067}, doi = {10.3390/ijms23042061}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284056}, year = {2022}, abstract = {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.}, language = {en} } @article{FernandezCastilloCabanaDominguezKappeletal.2021, author = {Fern{\`a}ndez-Castillo, No{\`e}lia and Cabana-Dom{\´i}nguez, Judit and Kappel, Djenifer B. and Torrico, B{\`a}rbara and Weber, Heike and Lesch, Klaus-Peter and Lao, Oscar and Reif, Andreas and Cormand, Bru}, title = {Exploring the contribution to ADHD of genes involved in Mendelian disorders presenting with hyperactivity and/or inattention}, series = {Genes}, volume = {13}, journal = {Genes}, number = {1}, issn = {2073-4425}, doi = {10.3390/genes13010093}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252346}, year = {2021}, abstract = {Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders.}, 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{SchapovalovaGorlovadeMunteretal.2022, author = {Schapovalova, Olesia and Gorlova, Anna and de Munter, Johannes and Sheveleva, Elisaveta and Eropkin, Mikhail and Gorbunov, Nikita and Sicker, Michail and Umriukhin, Aleksei and Lyubchyk, Sergiy and Lesch, Klaus-Peter and Strekalova, Tatyana and Schroeter, Careen A.}, title = {Immunomodulatory effects of new phytotherapy on human macrophages and TLR4- and TLR7/8-mediated viral-like inflammation in mice}, series = {Frontiers in Medicine}, volume = {9}, journal = {Frontiers in Medicine}, issn = {2296-858X}, doi = {10.3389/fmed.2022.952977}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286301}, year = {2022}, abstract = {Background While all efforts have been undertaken to propagate the vaccination and develop remedies against SARS-CoV-2, no satisfactory management of this infection is available yet. Moreover, poor availability of any preventive and treatment measures of SARS-CoV-2 in economically disadvantageous communities aggravates the course of the pandemic. Here, we studied a new immunomodulatory phytotherapy (IP), an extract of blackberry, chamomile, garlic, cloves, and elderberry as a potential low-cost solution for these problems given the reported efficacy of herbal medicine during the previous SARS virus outbreak. Methods The key feature of SARS-CoV-2 infection, excessive inflammation, was studied in in vitro and in vivo assays under the application of the IP. First, changes in tumor-necrosis factor (TNF) and lnteurleukin-1 beta (IL-1β) concentrations were measured in a culture of human macrophages following the lipopolysaccharide (LPS) challenge and treatment with IP or prednisolone. Second, chronically IP-pre-treated CD-1 mice received an agonist of Toll-like receptors (TLR)-7/8 resiquimod and were examined for lung and spleen expression of pro-inflammatory cytokines and blood formula. Finally, chronically IP-pre-treated mice challenged with LPS injection were studied for "sickness" behavior. Additionally, the IP was analyzed using high-potency-liquid chromatography (HPLC)-high-resolution-mass-spectrometry (HRMS). Results LPS-induced in vitro release of TNF and IL-1β was reduced by both treatments. The IP-treated mice displayed blunted over-expression of SAA-2, ACE-2, CXCL1, and CXCL10 and decreased changes in blood formula in response to an injection with resiquimod. The IP-treated mice injected with LPS showed normalized locomotion, anxiety, and exploration behaviors but not abnormal forced swimming. Isoquercitrin, choline, leucine, chlorogenic acid, and other constituents were identified by HPLC-HRMS and likely underlie the IP immunomodulatory effects. Conclusions Herbal IP-therapy decreases inflammation and, partly, "sickness behavior," suggesting its potency to combat SARS-CoV-2 infection first of all via its preventive effects.}, 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} } @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{LueffeD'OrazioBaueretal.2021, author = {L{\"u}ffe, Teresa M. and D'Orazio, Andrea and Bauer, Moritz and Gioga, Zoi and Schoeffler, Victoria and Lesch, Klaus-Peter and Romanos, Marcel and Drepper, Carsten and Lillesaar, Christina}, title = {Increased locomotor activity via regulation of GABAergic signalling in foxp2 mutant zebrafish - implications for neurodevelopmental disorders}, series = {Translational Psychiatry}, volume = {11}, journal = {Translational Psychiatry}, doi = {10.1038/s41398-021-01651-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-264713}, year = {2021}, abstract = {Recent advances in the genetics of neurodevelopmental disorders (NDDs) have identified the transcription factor FOXP2 as one of numerous risk genes, e.g. in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). FOXP2 function is suggested to be involved in GABAergic signalling and numerous studies demonstrate that GABAergic function is altered in NDDs, thus disrupting the excitation/inhibition balance. Interestingly, GABAergic signalling components, including glutamate-decarboxylase 1 (Gad1) and GABA receptors, are putative transcriptional targets of FOXP2. However, the specific role of FOXP2 in the pathomechanism of NDDs remains elusive. Here we test the hypothesis that Foxp2 affects behavioural dimensions via GABAergic signalling using zebrafish as model organism. We demonstrate that foxp2 is expressed by a subset of GABAergic neurons located in brain regions involved in motor functions, including the subpallium, posterior tuberculum, thalamus and medulla oblongata. Using CRISPR/Cas9 gene-editing we generated a novel foxp2 zebrafish loss-of-function mutant that exhibits increased locomotor activity. Further, genetic and/or pharmacological disruption of Gad1 or GABA-A receptors causes increased locomotor activity, resembling the phenotype of foxp2 mutants. Application of muscimol, a GABA-A receptor agonist, rescues the hyperactive phenotype induced by the foxp2 loss-of-function. By reverse translation of the therapeutic effect on hyperactive behaviour exerted by methylphenidate, we note that application of methylphenidate evokes different responses in wildtype compared to foxp2 or gad1b loss-of-function animals. Together, our findings support the hypothesis that foxp2 regulates locomotor activity via GABAergic signalling. This provides one targetable mechanism, which may contribute to behavioural phenotypes commonly observed in NDDs.}, language = {en} } @article{ZieglerRadtkeVitaleetal.2021, author = {Ziegler, Georg C. and Radtke, Franziska and Vitale, Maria Rosaria and Preuße, Andr{\´e} and Klopocki, Eva and Herms, Stefan and Lesch, Klaus-Peter}, title = {Generation of multiple human iPSC lines from peripheral blood mononuclear cells of two SLC2A3 deletion and two SLC2A3 duplication carriers}, series = {Stem Cell Research}, volume = {56}, journal = {Stem Cell Research}, doi = {10.1016/j.scr.2021.102526}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-264696}, year = {2021}, abstract = {Copy number variants of SLC2A3, which encodes the glucose transporter GLUT3, are associated with several neuropsychiatric and cardiac diseases. Here, we report the successful reprogramming of peripheral blood mononuclear cells from two SLC2A3 duplication and two SLC2A3 deletion carriers and subsequent generation of two transgene-free iPSC clones per donor by Sendai viral transduction. All eight clones represent bona fide hiPSCs with high expression of pluripotency genes, ability to differentiate into cells of all three germ layers and normal karyotype. The generated cell lines will be helpful to enlighten the role of glucometabolic alterations in pathophysiological processes shared across organ boundaries.}, language = {en} } @article{VitaleZoellerJanschetal.2021, author = {Vitale, Maria Rosaria and Z{\"o}ller, Johanna Eva Maria and Jansch, Charline and Janz, Anna and Edenhofer, Frank and Klopocki, Eva and van den Hove, Daniel and Vanmierlo, Tim and Rivero, Olga and Kasri, Nael Nadif and Ziegler, Georg Christoph and Lesch, Klaus-Peter}, title = {Generation of induced pluripotent stem cell (iPSC) lines carrying a heterozygous (UKWMPi002-A-1) and null mutant knockout (UKWMPi002-A-2) of Cadherin 13 associated with neurodevelopmental disorders using CRISPR/Cas9}, series = {Stem Cell Research}, volume = {51}, journal = {Stem Cell Research}, doi = {10.1016/j.scr.2021.102169}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260331}, year = {2021}, abstract = {Fibroblasts isolated from a skin biopsy of a healthy 46-year-old female were infected with Sendai virus containing the Yamanaka factors to produce transgene-free human induced pluripotent stem cells (iPSCs). CRISPR/Cas9 was used to generate isogenic cell lines with a gene dose-dependent deficiency of CDH13, a risk gene associated with neurodevelopmental and psychiatric disorders. Thereby, a heterozygous CDH13 knockout (CDH13\(^{+/-}\)) and a CDH13 null mutant (CDH13\(^{-/-}\)) iPSC line was obtained. All three lines showed expression of pluripotency-associated markers, the ability to differentiate into cells of the three germ layers in vitro, and a normal female karyotype.}, language = {en} }