@article{RiveroSeltenSichetal.2015, author = {Rivero, O and Selten, MM and Sich, S and Popp, S and Bacmeister, L and Amendola, E and Negwer, M and Schubert, D and Proft, F and Kiser, D and Schmitt, AG and Gross, C and Kolk, SM and Strekalova, T and van den Hove, D and Resink, TJ and Kasir, N Nadif and Lesch, KP}, title = {Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition}, series = {Translational Psychiatry}, volume = {5}, journal = {Translational Psychiatry}, number = {e655}, doi = {10.1038/tp.2015.152}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145218}, year = {2015}, abstract = {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.}, language = {en} } @article{KarabegGrauthoffKollertetal.2013, author = {Karabeg, Margherita M. and Grauthoff, Sandra and Kollert, Sina Y. and Weidner, Magdalena and Heiming, Rebecca S. and Jansen, Friederike and Popp, Sandy and Kaiser, Sylvia and Lesch, Klaus-Peter and Sachser, Norbert and Schmitt, Angelika G. and Lewejohann, Lars}, title = {5-HTT Deficiency Affects Neuroplasticity and Increases Stress Sensitivity Resulting in Altered Spatial Learning Performance in the Morris Water Maze but Not in the Barnes Maze}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {10}, doi = {10.1371/journal.pone.0078238}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129978}, pages = {e78238}, year = {2013}, abstract = {The purpose of this study was to evaluate whether spatial hippocampus-dependent learning is affected by the serotonergic system and stress. Therefore, 5-HTT knockout (-/-), heterozygous (+/-) and wildtype (+/+) mice were subjected to the Barnes maze (BM) and the Morris water maze (WM), the latter being discussed as more aversive. Additionally, immediate early gene (IEG) expression, hippocampal adult neurogenesis (aN), and blood plasma corticosterone were analyzed. While the performance of 5-HTT-/- mice in the BM was undistinguishable from both other genotypes, they performed worse in the WM. However, in the course of the repeated WM trials 5-HTT-/- mice advanced to wildtype level. The experience of a single trial of either the WM or the BM resulted in increased plasma corticosterone levels in all genotypes. After several trials 5-HTT-/- mice exhibited higher corticosterone concentrations compared with both other genotypes in both tests. Corticosterone levels were highest in 5-HTT-/- mice tested in the WM indicating greater aversiveness of the WM and a greater stress sensitivity of 5-HTT deficient mice. Quantitative immunohistochemistry in the hippocampus revealed increased cell counts positive for the IEG products cFos and Arc as well as for proliferation marker Ki67 and immature neuron marker NeuroD in 5-HTT-/- mice compared to 5-HTT+/+ mice, irrespective of the test. Most differences were found in the suprapyramidal blade of the dentate gyrus of the septal hippocampus. Ki67-immunohistochemistry revealed a genotype x environment interaction with 5-HTT genotype differences in na{\"i}ve controls and WM experience exclusively yielding more Ki67-positive cells in 5-HTT+/+ mice. Moreover, in 5-HTT-/- mice we demonstrate that learning performance correlates with the extent of aN. Overall, higher baseline IEG expression and increased an in the hippocampus of 5-HTT-/- mice together with increased stress sensitivity may constitute the neurobiological correlate of raised alertness, possibly impeding optimal learning performance in the more stressful WM.}, language = {en} } @article{WaiderPoppLangeetal.2017, author = {Waider, J and Popp, S and Lange, MD and Kern, R and Kolter, JF and Kobler, J and Donner, NC and Lowe, KR and Malzbender, JH and Brazell, CJ and Arnold, MR and Aboagye, B and Schmitt-B{\"o}hrer, A and Lowry, CA and Pape, HC and Lesch, KP}, title = {Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice}, series = {Translational Psychiatry}, volume = {7}, journal = {Translational Psychiatry}, number = {e1246}, doi = {10.1038/tp.2017.209}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170239}, year = {2017}, abstract = {Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutive Tph2 inactivation and consequential lack of 5-HT synthesis in Tph2 null mutant mice (Tph2\(^{-/-}\)) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed in Tph2 heterozygous mice (Tph\(^{+/-}\)) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based on Slc6a4 mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala.}, language = {en} } @article{HauerPoppTaheretal.2019, author = {Hauer, Nadine N. and Popp, Bernt and Taher, Leila and Vogl, Carina and Dhandapany, Perundurai S. and B{\"u}ttner, Christian and Uebe, Steffen and Sticht, Heinrich and Ferrazzi, Fulvia and Ekici, Arif B. and De Luca, Alessandro and Klinger, Patrizia and Kraus, Cornelia and Zweier, Christiane and Wiesener, Antje and Abou Jamra, Rami and Kunstmann, Erdmute and Rauch, Anita and Wieczorek, Dagmar and Jung, Anna-Marie and Rohrer, Tilman R. and Zenker, Martin and Doerr, Helmuth-Guenther and Reis, Andr{\´e} and Thiel, Christian T.}, title = {Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature}, series = {European Journal of Human Genetics}, volume = {27}, journal = {European Journal of Human Genetics}, doi = {10.1038/s41431-019-0362-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227899}, pages = {1061-1071}, year = {2019}, abstract = {Height is a heritable and highly heterogeneous trait. Short stature affects 3\% of the population and in most cases is genetic in origin. After excluding known causes, 67\% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36\%) independent families. Based on systematic characterization of variants and functional analysis including expression in chondrocytes, we classified 13 genes as strong candidates. Whereas variants in at least two families were detected for all 13 candidates, two genes had variants in 6 (UBR4) and 8 (LAMA5) families, respectively. To facilitate their characterization, we established a clustered network of 1025 known growth and short stature genes, which yielded 29 significantly enriched clusters, including skeletal system development, appendage development, metabolic processes, and ciliopathy. Eleven of the candidate genes mapped to 21 of these clusters, including CPZ, EDEM3, FBRS, IFT81, KCND1, PLXNA3, RASA3, SLC7A8, UBR4, USP45, and ZFHX3. Fifty additional growth-related candidates we identified await confirmation in other affected families. Our study identifies Mendelian forms of growth retardation as an important component of idiopathic short stature.}, language = {en} }