@article{OpitzSchuwerkPaulusetal.2021, author = {Opitz, Timm and Schuwerk, Tobias and Paulus, Markus and Kloo, Daniela and Osterhaus, Christopher and Lesch, Klaus-Peter and Sodian, Beate}, title = {No links between genetic variation and developing theory of mind: A preregistered replication attempt of candidate gene studies}, series = {Developmental Science}, volume = {24}, journal = {Developmental Science}, number = {5}, doi = {10.1111/desc.13100}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238812}, year = {2021}, abstract = {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.}, 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{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{RiveroAlhamaRibaKuetal.2021, author = {Rivero, Olga and Alhama-Riba, Judit and Ku, Hsing-Ping and Fischer, Matthias and Ortega, Gabriela and {\´A}lmos, P{\´e}ter and Diouf, David and van den Hove, Daniel and Lesch, Klaus-Peter}, title = {Haploinsufficiency of the Attention-Deficit/Hyperactivity Disorder Risk Gene St3gal3 in Mice Causes Alterations in Cognition and Expression of Genes Involved in Myelination and Sialylation}, series = {Frontiers in Genetics}, volume = {12}, journal = {Frontiers in Genetics}, issn = {1664-8021}, doi = {10.3389/fgene.2021.688488}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246855}, year = {2021}, abstract = {Genome wide association meta-analysis identified ST3GAL3, a gene encoding the beta-galactosidase-alpha-2,3-sialyltransferase-III, as a risk gene for attention-deficit/hyperactivity disorder (ADHD). Although loss-of-function mutations in ST3GAL3 are implicated in non-syndromic autosomal recessive intellectual disability (NSARID) and West syndrome, the impact of ST3GAL3 haploinsufficiency on brain function and the pathophysiology of neurodevelopmental disorders (NDDs), such as ADHD, is unknown. Since St3gal3 null mutant mice display severe developmental delay and neurological deficits, we investigated the effects of partial inactivation of St3gal3 in heterozygous (HET) knockout (St3gal3±) mice on behavior as well as expression of markers linked to myelination processes and sialylation pathways. Our results reveal that male St3gal3 HET mice display cognitive deficits, while female HET animals show increased activity, as well as increased cognitive control, compared to their wildtype littermates. In addition, we observed subtle alterations in the expression of several markers implicated in oligodendrogenesis, myelin formation, and protein sialylation as well as cell adhesion/synaptic target glycoproteins of ST3GAL3 in a brain region- and/or sex-specific manner. Taken together, our findings indicate that haploinsufficiency of ST3GAL3 results in a sex-dependent alteration of cognition, behavior and markers of brain plasticity.}, 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{deMunterPavlovGorlovaetal.2021, author = {de Munter, Johannes and Pavlov, Dmitrii and Gorlova, Anna and Sicker, Michael and Proshin, Andrey and Kalueff, Allan V. and Svistunov, Andrey and Kiselev, Daniel and Nedorubov, Andrey and Morozov, Sergey and Umriukhin, Aleksei and Lesch, Klaus-Peter and Strekalova, Tatyana and Schroeter, Careen A.}, title = {Increased Oxidative Stress in the Prefrontal Cortex as a Shared Feature of Depressive- and PTSD-Like Syndromes: Effects of a Standardized Herbal Antioxidant}, series = {Frontiers in Nutrition}, volume = {8}, journal = {Frontiers in Nutrition}, issn = {2296-861X}, doi = {10.3389/fnut.2021.661455}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236326}, year = {2021}, abstract = {Major depression (MD) and posttraumatic stress disorder (PTSD) share common brain mechanisms and treatment strategies. Nowadays, the dramatically developing COVID-19 situation unavoidably results in stress, psychological trauma, and high incidence of MD and PTSD. Hence, the importance of the development of new treatments for these disorders cannot be overstated. Herbal medicine appears to be an effective and safe treatment with fewer side effects than classic pharmaca and that is affordable in low-income countries. Currently, oxidative stress and neuroinflammation attract increasing attention as important mechanisms of MD and PTSD. We investigated the effects of a standardized herbal cocktail (SHC), an extract of clove, bell pepper, basil, pomegranate, nettle, and other plants, that was designed as an antioxidant treatment in mouse models of MD and PTSD. In the MD model of "emotional" ultrasound stress (US), mice were subjected to ultrasound frequencies of 16-20 kHz, mimicking rodent sounds of anxiety/despair and "neutral" frequencies of 25-45 kHz, for three weeks and concomitantly treated with SHC. US-exposed mice showed elevated concentrations of oxidative stress markers malondialdehyde and protein carbonyl, increased gene and protein expression of pro-inflammatory cytokines interleukin (IL)-1β and IL-6 and other molecular changes in the prefrontal cortex as well as weight loss, helplessness, anxiety-like behavior, and neophobia that were ameliorated by the SHC treatment. In the PTSD model of the modified forced swim test (modFST), in which a 2-day swim is followed by an additional swim on day 5, mice were pretreated with SHC for 16 days. Increases in the floating behavior and oxidative stress markers malondialdehyde and protein carbonyl in the prefrontal cortex of modFST-mice were prevented by the administration of SHC. Chromatography mass spectrometry revealed bioactive constituents of SHC, including D-ribofuranose, beta-D-lactose, malic, glyceric, and citric acids that can modulate oxidative stress, immunity, and gut and microbiome functions and, thus, are likely to be active antistress elements underlying the beneficial effects of SHC. Significant correlations of malondialdehyde concentration in the prefrontal cortex with altered measures of behavioral despair and anxiety-like behavior suggest that the accumulation of oxidative stress markers are a common biological feature of MD and PTSD that can be equally effectively targeted therapeutically with antioxidant therapy, such as the SHC investigated here.}, language = {en} }