TY - JOUR A1 - Rivero, O A1 - Selten, MM A1 - Sich, S A1 - Popp, S A1 - Bacmeister, L A1 - Amendola, E A1 - Negwer, M A1 - Schubert, D A1 - Proft, F A1 - Kiser, D A1 - Schmitt, AG A1 - Gross, C A1 - Kolk, SM A1 - Strekalova, T A1 - van den Hove, D A1 - Resink, TJ A1 - Kasir, N Nadif A1 - Lesch, KP T1 - Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition JF - Translational Psychiatry N2 - Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo) phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13\(^{-/-}\) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13\(^{-/-}\) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism. KW - genome-wide association KW - deficit hyperactivity disorder KW - psychiatric disorders KW - neurodevelopmental disorders KW - synaptic plasticity KW - response inhibition KW - positive interneurons KW - T-cadherin KW - long-term potentiation KW - attention deficit/hyperactivity disorder Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145218 VL - 5 IS - e655 ER - TY - JOUR A1 - Schraut, K. G. A1 - Jakob, S. B. A1 - Weidner, M. T. A1 - Schmitt, A. G. A1 - Scholz, C. J. A1 - Strekalova, T. A1 - El Hajj, N. A1 - Eijssen, L. M. T. A1 - Domschke, K. A1 - Reif, A. A1 - Haaf, T. A1 - Ortega, G. A1 - Steinbusch, H. W. M. A1 - Lesch, K. P. A1 - Van den Hove, D. L. T1 - Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice JF - Translational Psychiatry N2 - The serotonin transporter gene (5-HTT/SLC6A4)-linked polymorphic region has been suggested to have a modulatory role in mediating effects of early-life stress exposure on psychopathology rendering carriers of the low-expression short (s)-variant more vulnerable to environmental adversity in later life. The underlying molecular mechanisms of this gene-by-environment interaction are not well understood, but epigenetic regulation including differential DNA methylation has been postulated to have a critical role. Recently, we used a maternal restraint stress paradigm of prenatal stress (PS) in 5-HTT-deficient mice and showed that the effects on behavior and gene expression were particularly marked in the hippocampus of female 5-Htt+/- offspring. Here, we examined to which extent these effects are mediated by differential methylation of DNA. For this purpose, we performed a genome-wide hippocampal DNA methylation screening using methylated-DNA immunoprecipitation (MeDIP) on Affymetrix GeneChip Mouse Promoter 1.0 R arrays. Using hippocampal DNA from the same mice as assessed before enabled us to correlate gene-specific DNA methylation, mRNA expression and behavior. We found that 5-Htt genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes, a subset of which showed overlap with the expression profiles of the corresponding transcripts. For example, a differentially methylated region in the gene encoding myelin basic protein (Mbp) was associated with its expression in a 5-Htt-, PS- and 5-Htt × PS-dependent manner. Subsequent fine-mapping of this Mbp locus linked the methylation status of two specific CpG sites to Mbp expression and anxiety-related behavior. In conclusion, hippocampal DNA methylation patterns and expression profiles of female prenatally stressed 5-Htt+/- mice suggest that distinct molecular mechanisms, some of which are promoter methylation-dependent, contribute to the behavioral effects of the 5-Htt genotype, PS exposure and their interaction. KW - mice KW - DNA Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119199 VL - 4 ER - TY - JOUR A1 - Cox-Limpens, Kimberly E. M. A1 - Vles, Johan S. H. A1 - van den Hove, Daniel L. A. A1 - Zimmermann, Luc Ji A1 - Gavilanes, Antonio W. D. T1 - Fetal asphyctic preconditioning alters the transcriptional response to perinatal asphyxia JF - BMC Neuroscience N2 - Background: Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of brain preconditioning. Unraveling mechanisms of this endogenous neuroprotection, activated by preconditioning, is an important step towards new clinical strategies for treating asphyctic neonates. Therefore, we investigated whole-genome transcriptional changes in the brain of rats which underwent perinatal asphyxia (PA), and rats where PA was preceded by fetal asphyctic preconditioning (FAPA). Offspring were sacrificed 6 h and 96 h after birth, and whole-genome transcription was investigated using the Affymetrix Gene1.0ST chip. Microarray data were analyzed with the Bioconductor Limma package. In addition to univariate analysis, we performed Gene Set Enrichment Analysis (GSEA) in order to derive results with maximum biological relevance. Results: We observed minimal, 25% or less, overlap of differentially regulated transcripts across different experimental groups which leads us to conclude that the transcriptional phenotype of these groups is largely unique. In both the PA and FAPA group we observe an upregulation of transcripts involved in cellular stress. Contrastingly, transcripts with a function in the cell nucleus were mostly downregulated in PA animals, while we see considerable upregulation in the FAPA group. Furthermore, we observed that histone deacetylases (HDACs) are exclusively regulated in FAPA animals. Conclusions: This study is the first to investigate whole-genome transcription in the neonatal brain after PA alone, and after perinatal asphyxia preceded by preconditioning (FAPA). We describe several genes/pathways, such as ubiquitination and proteolysis, which were not previously linked to preconditioning-induced neuroprotection. Furthermore, we observed that the majority of upregulated genes in preconditioned animals have a function in the cell nucleus, including several epigenetic players such as HDACs, which suggests that epigenetic mechanisms are likely to play a role in preconditioning-induced neuroprotection. KW - Perinatal Asphyxia KW - oxidative stress KW - microarray KW - cerebral artery occlusion KW - ischemic brain injury KW - genomic response KW - protein aggregation KW - immediate early genes KW - neuroprotection KW - tolerance KW - rat KW - expression KW - transient global ischemia KW - ubiquitination KW - epigenetics KW - fetal preconditioning KW - neonatal brain Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116185 VL - 15 ER - TY - JOUR A1 - Rutten, BPF A1 - Vermetten, E A1 - Vinkers, CH A1 - Ursini, G A1 - Daskalakis, NP A1 - Pishva, E A1 - de Nijs, L A1 - Houtepen, LC A1 - Eijssen, L A1 - Jaffe, AE A1 - Kenis, G A1 - Viechtbauer, W A1 - van den Hove, D A1 - Schraut, KG A1 - Lesch, K-P A1 - Kleinman, JE A1 - Hyde, TM A1 - Weinberger, DR A1 - Schalkwyk, L A1 - Lunnon, K A1 - Mill, J A1 - Cohen, H A1 - Yehuda, R A1 - Baker, DG A1 - Maihofer, AX A1 - Nievergelt, CM A1 - Geuze, E A1 - Boks, MPM T1 - Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder JF - Molecular Psychiatry N2 - In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n = 93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n = 98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD. KW - Molecular biology KW - Psychiatric disorders Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227171 VL - 23 IS - 5 ER -