TY - JOUR A1 - Kittel-Schneider, Sarah A1 - Kenis, Gunter A1 - Schek, Julia A1 - van den Hove, Daniel A1 - Prickaerts, Jos A1 - Lesch, Klaus-Peter A1 - Steinbusch, Harry A1 - Reif, Andreas T1 - Expression of monoamine transporters, nitric oxide synthase 3, and neurotrophin genes in antidepressant-stimulated astrocytes JF - Frontiers in Psychiatry N2 - Background: There is increasing evidence that glial cells play a role in the pathomechanisms of mood disorders and the mode of action of antidepressant drugs. Methods: To examine whether there is a direct effect on the expression of different genes encoding proteins that have been implicated in the pathophysiology of affective disorders, primary astrocyte cell cultures from rats were treated with two different antidepressant drugs, imipramine and escitalopram, and the RNA expression of brain-derived neurotrophic factor (Bdnf), serotonin transporter (5Htt), dopamine transporter (Dat), and endothelial nitric oxide synthase (Nos3) was examined. Results: Stimulation of astroglial cell culture with imipramine, a tricyclic antidepressant, led to a significant increase of the Bdnf RNA level whereas treatment with escitalopram did not. In contrast, 5Htt was not differentially expressed after antidepressant treatment. Finally, neither Dat nor Nos3 RNA expression was detected in cultured astrocytes. Conclusion: These data provide further evidence for a role of astroglial cells in the molecular mechanisms of action of antidepressants. KW - monoamine transporters KW - BDNF KW - geneexpression KW - astrocytes KW - glia KW - depression KW - antidepressant KW - mechanismofaction KW - nitricoxidesynthase Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123627 VL - 3 ER - TY - JOUR A1 - Pishva, Ehsan A1 - Drukker, Marjan A1 - Viechtbauer, Wolfgang A1 - Decoster, Jeroen A1 - Collip, Dina A1 - van Winkel, Ruud A1 - Wichers, Marieke A1 - Jacobs, Nele A1 - Thiery, Evert A1 - Derom, Catherine A1 - Geschwind, Nicole A1 - van den Hove, Daniel A1 - Lataster, Tineke A1 - Myin-Germeys, Inez A1 - van Os, Jim A1 - Rutten, Bart P. F. A1 - Kenis, Gunter T1 - Epigenetic Genes and Emotional Reactivity to Daily Life Events: A Multi-Step Gene-Environment Interaction Study JF - PLOS ONE N2 - Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery. KW - DNA methylation KW - de-novo methylation KW - psychotic experiences KW - DNMT3A KW - glucocorticoid receptor KW - stress KW - mammalian development KW - psychiatry KW - cortisol KW - cells Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115956 SN - 1932-6203 VL - 9 IS - 6 ER - TY - JOUR A1 - Gutknecht, Lise A1 - Popp, Sandy A1 - Waider, Jonas A1 - Sommerlandt, Frank M. J. A1 - Göppner, Corinna A1 - Post, Antonia A1 - Reif, Andreas A1 - van den Hove, Daniel A1 - Strekalova, Tatyana A1 - Schmitt, Angelika A1 - Colaςo, Maria B. N. A1 - Sommer, Claudia A1 - Palme, Rupert A1 - Lesch, Klaus-Peter T1 - Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice JF - Psychopharmacology N2 - Rationale While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation. Objective Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene. Results Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2\(^{−/−}\)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2\(^{−/−}\) males displayed increased impulsivity and high aggressiveness. Tph2\(^{−/−}\) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2\(^{−/−}\) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner. Conclusions Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality. KW - Serotonin KW - Tryptophan hydroxylase-2 (Tph2) KW - chronic stress KW - gene-by-environment interaction KW - anxiety KW - fear KW - depression KW - aggression Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154586 VL - 232 SP - 2429 EP - 2441 ER - TY - JOUR A1 - Vangeel, Elise Beau A1 - Pishva, Ehsan A1 - Hompes, Titia A1 - van den Hove, Daniel A1 - Lambrechts, Diether A1 - Allegaert, Karel A1 - Freson, Kathleen A1 - Izzi, Benedetta A1 - Claes, Stephan T1 - Newborn genome-wide DNA methylation in association with pregnancy anxiety reveals a potential role for \(GABBR1\) JF - Clinical Epigenetics N2 - Background: There is increasing evidence for the role of prenatal stress in shaping offspring DNA methylation and disease susceptibility. In the current study, we aimed to identify genes and pathways associated with pregnancy anxiety using a genome-wide DNA methylation approach. Methods: We selected 22 versus 23 newborns from our Prenatal Early Life Stress (PELS) cohort, exposed to the lowest or highest degree of maternal pregnancy anxiety, respectively. Cord blood genome-wide DNA methylation was assayed using the HumanMethylation450 BeadChip (HM450, n = 45) and candidate gene methylation using EpiTYPER (n = 80). Cortisol levels were measured at 2, 4, and 12 months of age to test infant stress system (re)activity. Results: Data showed ten differentially methylated regions (DMR) when comparing newborns exposed to low versus high pregnancy anxiety scores. We validated a top DMR in the GABA-B receptor subunit 1 gene (GABBR1) revealing the association with pregnancy anxiety particularly in male newborns (most significant CpG Pearson R = 0.517, p = 0.002; average methylation Pearson R = 0.332, p = 0.039). Cord blood GABBR1 methylation was associated with infant cortisol levels in response to a routine vaccination at 4 months old. Conclusions: In conclusion, our results show that pregnancy anxiety is associated with differential DNA methylation patterns in newborns and that our candidate gene GABBR1 is associated with infant hypothalamic-pituitary-adrenal axis response to a stressor. Our findings reveal a potential role for GABBR1 methylation in association with stress and provide grounds for further research. KW - DNA methylation KW - GABBR1 KW - gender differences KW - HPA axis KW - pregnancy anxiety KW - prenatal stress Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173825 VL - 9 ER - TY - JOUR A1 - Tiane, Assia A1 - Schepers, Melissa A1 - Rombaut, Ben A1 - Hupperts, Raymond A1 - Prickaerts, Jos A1 - Hellings, Niels A1 - van den Hove, Daniel A1 - Vanmierlo, Tim T1 - From OPC to oligodendrocyte: an epigenetic journey JF - Cells N2 - Oligodendrocytes provide metabolic and functional support to neuronal cells, rendering them key players in the functioning of the central nervous system. Oligodendrocytes need to be newly formed from a pool of oligodendrocyte precursor cells (OPCs). The differentiation of OPCs into mature and myelinating cells is a multistep process, tightly controlled by spatiotemporal activation and repression of specific growth and transcription factors. While oligodendrocyte turnover is rather slow under physiological conditions, a disruption in this balanced differentiation process, for example in case of a differentiation block, could have devastating consequences during ageing and in pathological conditions, such as multiple sclerosis. Over the recent years, increasing evidence has shown that epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNAs, are major contributors to OPC differentiation. In this review, we discuss how these epigenetic mechanisms orchestrate and influence oligodendrocyte maturation. These insights are a crucial starting point for studies that aim to identify the contribution of epigenetics in demyelinating diseases and may thus provide new therapeutic targets to induce myelin repair in the long run. KW - oligodendrocyte KW - epigenetics KW - myelination Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193267 SN - 2073-4409 VL - 8 IS - 10 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 - 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 -