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  - Fernàndez-Castillo, Noèlia
A1  - Cabana-Domínguez, Judit
A1  - Kappel, Djenifer B.
A1  - Torrico, Bàrbara
A1  - Weber, Heike
A1  - Lesch, Klaus-Peter
A1  - Lao, Oscar
A1  - Reif, Andreas
A1  - Cormand, Bru
T1  - Exploring the contribution to ADHD of genes involved in Mendelian disorders presenting with hyperactivity and/or inattention
JF  - Genes
N2  - 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.
KW  - ADHD
KW  - rare mendelian disorders
KW  - genetic variants
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252346
SN  - 2073-4425
VL  - 13
IS  - 1
ER  - 
TY  - JOUR
A1  - Popp, Sandy
A1  - Schmitt-Böhrer, Angelika
A1  - Langer, Simon
A1  - Hofmann, Ulrich
A1  - Hommers, Leif
A1  - Schuh, Kai
A1  - Frantz, Stefan
A1  - Lesch, Klaus-Peter
A1  - Frey, Anna
T1  - 5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction
JF  - Journal of Clinical Medicine
N2  - Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally naïve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (−/−) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT−/− mice with infarct sizes >30% experienced 100% mortality, while 50% of 5-HTT+/− and 37% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30%) 5-HTT−/− mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT−/− mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.
KW  - chronic heart failure
KW  - myocardial infarction
KW  - serotonin transporter deficient mice
KW  - anxiety
KW  - depression
KW  - behavior
KW  - inflammation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242739
SN  - 2077-0383
VL  - 10
IS  - 14
ER  - 
TY  - JOUR
A1  - Jansch, Charline
A1  - Ziegler, Georg C.
A1  - Forero, Andrea
A1  - Gredy, Sina
A1  - Wäldchen, Sina
A1  - Vitale, Maria Rosaria
A1  - Svirin, Evgeniy
A1  - Zöller, Johanna E. M.
A1  - Waider, Jonas
A1  - Günther, Katharina
A1  - Edenhofer, Frank
A1  - Sauer, Markus
A1  - Wischmeyer, Erhard
A1  - Lesch, Klaus-Peter
T1  - Serotonin-specific neurons differentiated from human iPSCs form distinct subtypes with synaptic protein assembly
JF  - Journal of Neural Transmission
N2  - 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.
KW  - neuropsychiatric disorders
KW  - human induced pluripotent stem cell (hiPSC)
KW  - serotonin-specific neurons
KW  - median and dorsal raphe
KW  - synapse formation
KW  - Cadherin-13 (CDH13)
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268519
SN  - 1435-1463
VL  - 128
IS  - 2
ER  - 
TY  - JOUR
A1  - Rivero, Olga
A1  - Alhama-Riba, Judit
A1  - Ku, Hsing-Ping
A1  - Fischer, Matthias
A1  - Ortega, Gabriela
A1  - Álmos, Péter
A1  - Diouf, David
A1  - van den Hove, Daniel
A1  - Lesch, Klaus-Peter
T1  - 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
JF  - Frontiers in Genetics
N2  - 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.
KW  - sialyltransferase
KW  - sialic acid
KW  - psychiatric disorders
KW  - attention-deficit/hyperactivity disorder (ADHD)
KW  - prefrontal cortex
KW  - hippocampus
KW  - mouse model
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246855
SN  - 1664-8021
VL  - 12
ER  - 
TY  - JOUR
A1  - Postema, Merel C.
A1  - Hoogman, Martine
A1  - Ambrosino, Sara
A1  - Asherson, Philip
A1  - Banaschewski, Tobias
A1  - Bandeira, Cibele E.
A1  - Baranov, Alexandr
A1  - Bau, Claiton H.D.
A1  - Baumeister, Sarah
A1  - Baur‐Streubel, Ramona
A1  - Bellgrove, Mark A.
A1  - Biederman, Joseph
A1  - Bralten, Janita
A1  - Brandeis, Daniel
A1  - Brem, Silvia
A1  - Buitelaar, Jan K.
A1  - Busatto, Geraldo F.
A1  - Castellanos, Francisco X.
A1  - Cercignani, Mara
A1  - Chaim‐Avancini, Tiffany M.
A1  - Chantiluke, Kaylita C.
A1  - Christakou, Anastasia
A1  - Coghill, David
A1  - Conzelmann, Annette
A1  - Cubillo, Ana I.
A1  - Cupertino, Renata B.
A1  - de Zeeuw, Patrick
A1  - Doyle, Alysa E.
A1  - Durston, Sarah
A1  - Earl, Eric A.
A1  - Epstein, Jeffery N.
A1  - Ethofer, Thomas
A1  - Fair, Damien A.
A1  - Fallgatter, Andreas J.
A1  - Faraone, Stephen V.
A1  - Frodl, Thomas
A1  - Gabel, Matt C.
A1  - Gogberashvili, Tinatin
A1  - Grevet, Eugenio H.
A1  - Haavik, Jan
A1  - Harrison, Neil A.
A1  - Hartman, Catharina A.
A1  - Heslenfeld, Dirk J.
A1  - Hoekstra, Pieter J.
A1  - Hohmann, Sarah
A1  - Høvik, Marie F.
A1  - Jernigan, Terry L.
A1  - Kardatzki, Bernd
A1  - Karkashadze, Georgii
A1  - Kelly, Clare
A1  - Kohls, Gregor
A1  - Konrad, Kerstin
A1  - Kuntsi, Jonna
A1  - Lazaro, Luisa
A1  - Lera‐Miguel, Sara
A1  - Lesch, Klaus‐Peter
A1  - Louza, Mario R.
A1  - Lundervold, Astri J.
A1  - Malpas, Charles B
A1  - Mattos, Paulo
A1  - McCarthy, Hazel
A1  - Namazova‐Baranova, Leyla
A1  - Nicolau, Rosa
A1  - Nigg, Joel T.
A1  - Novotny, Stephanie E.
A1  - Oberwelland Weiss, Eileen
A1  - O'Gorman Tuura, Ruth L.
A1  - Oosterlaan, Jaap
A1  - Oranje, Bob
A1  - Paloyelis, Yannis
A1  - Pauli, Paul
A1  - Picon, Felipe A.
A1  - Plessen, Kerstin J.
A1  - Ramos‐Quiroga, J. Antoni
A1  - Reif, Andreas
A1  - Reneman, Liesbeth
A1  - Rosa, Pedro G.P.
A1  - Rubia, Katya
A1  - Schrantee, Anouk
A1  - Schweren, Lizanne J.S.
A1  - Seitz, Jochen
A1  - Shaw, Philip
A1  - Silk, Tim J.
A1  - Skokauskas, Norbert
A1  - Soliva Vila, Juan C.
A1  - Stevens, Michael C.
A1  - Sudre, Gustavo
A1  - Tamm, Leanne
A1  - Tovar‐Moll, Fernanda
A1  - van Erp, Theo G.M.
A1  - Vance, Alasdair
A1  - Vilarroya, Oscar
A1  - Vives‐Gilabert, Yolanda
A1  - von Polier, Georg G.
A1  - Walitza, Susanne
A1  - Yoncheva, Yuliya N.
A1  - Zanetti, Marcus V.
A1  - Ziegler, Georg C.
A1  - Glahn, David C.
A1  - Jahanshad, Neda
A1  - Medland, Sarah E.
A1  - Thompson, Paul M.
A1  - Fisher, Simon E.
A1  - Franke, Barbara
A1  - Francks, Clyde
T1  - Analysis of structural brain asymmetries in attention‐deficit/hyperactivity disorder in 39 datasets
JF  - Journal of Child Psychology and Psychiatry
N2  - Objective
Some studies have suggested alterations of structural brain asymmetry in attention‐deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left‐right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.

Methods
We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.

Results
There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study‐wide correction for multiple testing.

Conclusion
Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
KW  - attention‐deficit
KW  - hyperactivity disorder
KW  - brain asymmetry
KW  - brain laterality
KW  - structural MRI
KW  - large‐scale data
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239968
VL  - 62
IS  - 10
SP  - 1202
EP  - 1219
ER  - 
TY  - JOUR
A1  - Ziegler, Georg C.
A1  - Ehlis, Ann-Christine
A1  - Weber, Heike
A1  - Vitale, Maria Rosaria
A1  - Zöller, Johanna E. M.
A1  - Ku, Hsing-Ping
A1  - Schiele, Miriam A.
A1  - Kürbitz, Laura I.
A1  - Romanos, Marcel
A1  - Pauli, Paul
A1  - Kalisch, Raffael
A1  - Zwanzger, Peter
A1  - Domschke, Katharina
A1  - Fallgatter, Andreas J.
A1  - Reif, Andreas
A1  - Lesch, Klaus-Peter
T1  - A Common CDH13 Variant is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD
JF  - Genes
N2  - The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
KW  - ADHD
KW  - CDH13
KW  - neurodevelopment
KW  - executive functions
KW  - working memory
KW  - Big Five
KW  - agreeableness
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245220
SN  - 2073-4425
VL  - 12
IS  - 9
ER  - 
TY  - JOUR
A1  - Lüffe, Teresa M.
A1  - D'Orazio, Andrea
A1  - Bauer, Moritz
A1  - Gioga, Zoi
A1  - Schoeffler, Victoria
A1  - Lesch, Klaus-Peter
A1  - Romanos, Marcel
A1  - Drepper, Carsten
A1  - Lillesaar, Christina
T1  - Increased locomotor activity via regulation of GABAergic signalling in foxp2 mutant zebrafish – implications for neurodevelopmental disorders
JF  - Translational Psychiatry
N2  - 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.
KW  - comparative genomics
KW  - molecular neuroscience
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264713
VL  - 11
ER  - 
TY  - JOUR
A1  - Vitale, Maria Rosaria
A1  - Zöller, Johanna Eva Maria
A1  - Jansch, Charline
A1  - Janz, Anna
A1  - Edenhofer, Frank
A1  - Klopocki, Eva
A1  - van den Hove, Daniel
A1  - Vanmierlo, Tim
A1  - Rivero, Olga
A1  - Kasri, Nael Nadif
A1  - Ziegler, Georg Christoph
A1  - Lesch, Klaus-Peter
T1  - 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
JF  - Stem Cell Research
N2  - 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.
KW  - CRISPR-Cas Systems
KW  - cadherins
KW  - female
KW  - heterozygote
KW  - humans
KW  - Induced Pluripotent Stem Cells
KW  - middle aged
KW  - neurodevelopmental disorders / genetics
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260331
VL  - 51
ER  - 
TY  - JOUR
A1  - de Munter, Johannes
A1  - Pavlov, Dmitrii
A1  - Gorlova, Anna
A1  - Sicker, Michael
A1  - Proshin, Andrey
A1  - Kalueff, Allan V.
A1  - Svistunov, Andrey
A1  - Kiselev, Daniel
A1  - Nedorubov, Andrey
A1  - Morozov, Sergey
A1  - Umriukhin, Aleksei
A1  - Lesch, Klaus-Peter
A1  - Strekalova, Tatyana
A1  - Schroeter, Careen A.
T1  - Increased Oxidative Stress in the Prefrontal Cortex as a Shared Feature of Depressive- and PTSD-Like Syndromes: Effects of a Standardized Herbal Antioxidant
JF  - Frontiers in Nutrition
N2  - 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.
KW  - antioxidant nutrients
KW  - oxidative stress
KW  - depression
KW  - post-traumatic stress disorder
KW  - pro-inflammatory cytokines
KW  - prefrontal cortex
KW  - forced swimming
KW  - mice
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236326
SN  - 2296-861X
VL  - 8
ER  - 
TY  - JOUR
A1  - Ziegler, Georg C.
A1  - Radtke, Franziska
A1  - Vitale, Maria Rosaria
A1  - Preuße, André
A1  - Klopocki, Eva
A1  - Herms, Stefan
A1  - Lesch, Klaus-Peter
T1  - Generation of multiple human iPSC lines from peripheral blood mononuclear cells of two SLC2A3 deletion and two SLC2A3 duplication carriers
JF  - Stem Cell Research
N2  - 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.
KW  - congenital heart-deffects
KW  - transporter gene SLC2A3
KW  - copy-number variation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264696
VL  - 56
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  - 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  - 
TY  - JOUR
A1  - Schapovalova, Olesia
A1  - Gorlova, Anna
A1  - de Munter, Johannes
A1  - Sheveleva, Elisaveta
A1  - Eropkin, Mikhail
A1  - Gorbunov, Nikita
A1  - Sicker, Michail
A1  - Umriukhin, Aleksei
A1  - Lyubchyk, Sergiy
A1  - Lesch, Klaus-Peter
A1  - Strekalova, Tatyana
A1  - Schroeter, Careen A.
T1  - Immunomodulatory effects of new phytotherapy on human macrophages and TLR4- and TLR7/8-mediated viral-like inflammation in mice
JF  - Frontiers in Medicine
N2  - 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.
KW  - toll-like receptors
KW  - SARS-CoV-2
KW  - inflammation
KW  - pro-inflammatory cytokines
KW  - mice
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286301
SN  - 2296-858X
VL  - 9
ER  - 
TY  - JOUR
A1  - Gorlova, Anna
A1  - Svirin, Evgeniy
A1  - Pavlov, Dmitrii
A1  - Cespuglio, Raymond
A1  - Proshin, Andrey
A1  - Schroeter, Careen A.
A1  - Lesch, Klaus-Peter
A1  - Strekalova, Tatyana
T1  - Understanding the role of oxidative stress, neuroinflammation and abnormal myelination in excessive aggression associated with depression: recent input from mechanistic studies
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - major depressive disorder (MDD)
KW  - aggression
KW  - neuroinflammation
KW  - oxidative stress
KW  - insulin receptor
KW  - myelination
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304917
SN  - 1422-0067
VL  - 24
IS  - 2
ER  -