@article{GutknechtPoppWaideretal.2015,
  author    = {Gutknecht, Lise and Popp, Sandy and Waider, Jonas and Sommerlandt, Frank M. J. and G{\"o}ppner, Corinna and Post, Antonia and Reif, Andreas and van den Hove, Daniel and Strekalova, Tatyana and Schmitt, Angelika and Colaςo, Maria B. N. and Sommer, Claudia and Palme, Rupert and Lesch, Klaus-Peter},
  title     = {Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice},
  series = {Psychopharmacology},
  volume    = {232},
  journal   = {Psychopharmacology},
  doi       = {10.1007/s00213-015-3879-0},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154586},
  pages     = {2429 -- 2441},
  year      = {2015},
  abstract  = {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.},
  language  = {en}
}
@phdthesis{Waider2012,
  author    = {Waider, Jonas},
  title     = {The effects of serotonin deficiency in mice: Focus on the GABAergic system},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-74565},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Based on genetic association and functional imaging studies, reduced function of tryptophan hydroxylase-2 (TPH2) has been shown to be critically involved in the pathophysiology of anxiety-disorders and depression. In order to elucidate the impact of a complete neuronal 5-HT deficiency, mice with a targeted inactivation of the gene encoding Tph2 were generated. Interestingly, survival of Tph2-/- mice, the formation of serotonergic neurons and the pathfinding of their projections was not impaired. Within this thesis, I investigated the influence of 5-HT deficiency on the γ-amino butyric acid (GABA) system. The GABAergic system is implicated in the pathophysiology of anxiety disorders. Therefore, measurement of GABA concentrations in different limbic brain regions was carried out. These measurements were combined with immunohistochemical estimation of GABAergic cell subpopulations in the dorsal hippocampus and amygdala. In Tph2-/- mice GABA concentrations were increased exclusively in the dorsal hippocampus. In heterozygous Tph2+/- mice concentrations of GABA were increased in the amygdala compared to Tph2-/- and wt control mice, while the reverse was found in the prefrontal cortex. The changes in GABA concentrations were accompanied by altered cell density of GABAergic neurons within the basolateral complex of the amygdala and parvalbumin (PV) neurons of the dorsal hippocampus and by adaptational changes of 5-HT receptors. Thus, adaptive changes during the development on the GABA system may reflect altered anxiety-like and depressive-like behavior in adulthood. Moreover, chronic mild stress (CMS) rescues the depressive-like effects induced by 5-HT deficiency. In contrast, 5-HT is important in mediating an increased innate anxiety-like behavior under CMS conditions. This is in line with a proposed dual role of 5-HT acting through different mechanisms on anxiety and depressive-like behavior, which is influenced by gene-environment interaction effects. Further research is needed to disentangle these complex networks in the future.},
  subject      = {Knockout <Molekulargenetik>},
  language  = {en}
}
@article{GutknechtAraragiMerkeretal.2012,
  author    = {Gutknecht, Lise and Araragi, Naozumi and Merker, S{\"o}ren and Waider, Jonas and Sommerlandt, Frank M. J. and Mlinar, Boris and Baccini, Gilda and Mayer, Ute and Proft, Florian and Hamon, Michel and Schmitt, Angelika G. and Corradetti, Renato and Lanfumey, Laurence and Lesch, Klaus-Peter},
  title     = {Impacts of Brain Serotonin Deficiency following Tph2 Inactivation on Development and Raphe Neuron Serotonergic Specification},
  series = {PLoS One},
  volume    = {7},
  journal   = {PLoS One},
  number    = {8},
  doi       = {10.1371/journal.pone.0043157},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133728},
  year      = {2012},
  abstract  = {Brain serotonin (5-HT) is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2). Tph2 inactivation (Tph2-/-) resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/- mice. The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT) demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification. Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons. Moreover, 5-HT deficiency induces an up-regulation of 5-HT\(_{1A}\) and 5-HT\(_{1B}\) receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis.},
  language  = {en}
}
@article{WaiderPoppMlinaretal.2019,
  author    = {Waider, Jonas and Popp, Sandy and Mlinar, Boris and Montalbano, Alberto and Bonfiglio, Francesco and Aboagye, Benjamin and Thuy, Elisabeth and Kern, Raphael and Thiel, Christopher and Araragi, Naozumi and Svirin, Evgeniy and Schmitt-B{\"o}hrer, Angelika G. and Corradetti, Renato and Lowry, Christopher A. and Lesch, Klaus-Peter},
  title     = {Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity},
  series = {Frontiers in Neuroscience},
  volume    = {13},
  journal   = {Frontiers in Neuroscience},
  number    = {245},
  issn      = {1662-453X},
  doi       = {10.3389/fnins.2019.00245},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196077},
  year      = {2019},
  abstract  = {Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.},
  language  = {en}
}
@article{FereroRiveroWaeldchenetal.2017,
  author    = {Ferero, Andrea and Rivero, Olga and W{\"a}ldchen, Sina and Ku, Hsing-Ping and Kiser, Dominik P. and G{\"a}rtner, Yvonne and Pennington, Laura S. and Waider, Jonas and Gaspar, Patricia and Jansch, Charline and Edenhofer, Frank and Resink, Th{\´e}r{\`e}se J. and Blum, Robert and Sauer, Markus and Lesch, Klaus-Peter},
  title     = {Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain},
  series = {Frontiers in Cellular Neuroscience},
  volume    = {11},
  journal   = {Frontiers in Cellular Neuroscience},
  number    = {307},
  doi       = {10.3389/fncel.2017.00307},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170313},
  year      = {2017},
  abstract  = {Background: During early prenatal stages of brain development, serotonin (5-HT)-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR), innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13) has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system. Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency. Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs), which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5. Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell density of the developing DR and the posterior innervation of the prefrontal cortex (PFC), and therefore might be involved in the migration, axonal outgrowth and terminal target finding of DR 5-HT neurons. Dysregulation of CDH13 expression may thus contribute to alterations in this system of neurotransmission, impacting cognitive function, which is frequently impaired in neurodevelopmental disorders including attention-deficit/hyperactivity and autism spectrum disorders.},
  language  = {en}
}
@article{JanschZieglerForeroetal.2021,
  author    = {Jansch, Charline and Ziegler, Georg C. and Forero, Andrea and Gredy, Sina and W{\"a}ldchen, Sina and Vitale, Maria Rosaria and Svirin, Evgeniy and Z{\"o}ller, Johanna E. M. and Waider, Jonas and G{\"u}nther, Katharina and Edenhofer, Frank and Sauer, Markus and Wischmeyer, Erhard and Lesch, Klaus-Peter},
  title     = {Serotonin-specific neurons differentiated from human iPSCs form distinct subtypes with synaptic protein assembly},
  series = {Journal of Neural Transmission},
  volume    = {128},
  journal   = {Journal of Neural Transmission},
  number    = {2},
  issn      = {1435-1463},
  doi       = {10.1007/s00702-021-02303-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-268519},
  pages     = {225-241},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{JanschGuentherWaideretal.2018,
  author    = {Jansch, Charline and G{\"u}nther, Katharina and Waider, Jonas and Ziegler, Georg C. and Forero, Andrea and Kollert, Sina and Svirin, Evgeniy and P{\"u}hringer, Dirk and Kwok, Chee Keong and Ullmann, Reinhard and Maierhofer, Anna and Flunkert, Julia and Haaf, Thomas and Edenhofer, Frank and Lesch, Klaus-Peter},
  title     = {Generation of a human induced pluripotent stem cell (iPSC) line from a 51-year-old female with attention-deficit/hyperactivity disorder (ADHD) carrying a duplication of SLC2A3},
  series = {Stem Cell Research},
  volume    = {28},
  journal   = {Stem Cell Research},
  doi       = {10.1016/j.scr.2018.02.005},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176654},
  pages     = {136-140},
  year      = {2018},
  abstract  = {Fibroblasts were isolated from a skin biopsy of a clinically diagnosed 51-year-old female attention-deficit/hyperactivity disorder (ADHD) patient carrying a duplication of SLC2A3, a gene encoding neuronal glucose transporter-3 (GLUT3). Patient fibroblasts were infected with Sendai virus, a single-stranded RNA virus, to generate transgene-free human induced pluripotent stem cells (iPSCs). SLC2A3-D2-iPSCs showed expression of pluripotency-associated markers, were able to differentiate into cells of the three germ layers in vitro and had a normal female karyotype. This in vitro cellular model can be used to study the role of risk genes in the pathogenesis of ADHD, in a patient-specific manner.},
  language  = {en}
}
@article{WeidnerLardenoijeEijssenetal.2019,
  author    = {Weidner, Magdalena T. and Lardenoije, Roy and Eijssen, Lars and Mogavero, Floriana and De Groodt, Lilian P. M. T. and Popp, Sandy and Palme, Rupert and F{\"o}rstner, Konrad U. and Strekalova, Tatyana and Steinbusch, Harry W. M. and Schmitt-B{\"o}hrer, Angelika G. and Glennon, Jeffrey C. and Waider, Jonas and van den Hove, Daniel L. A. and Lesch, Klaus-Peter},
  title     = {Identification of cholecystokinin by genome-wide profiling as potential mediator of serotonin-dependent behavioral effects of maternal separation in the amygdala},
  series = {Frontiers in Neuroscience},
  volume    = {13},
  journal   = {Frontiers in Neuroscience},
  doi       = {10.3389/fnins.2019.00460},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201340},
  pages     = {460},
  year      = {2019},
  abstract  = {Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2\(^{-/-}\)) and heterozygous (Tph2\(^{+/-}\)) mice, and their wildtype littermates (Tph2\(^{+/+}\)) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2\(^{-/-}\) mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2\(^{+/-}\) mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2\(^{+/-}\) mice when compared to their Tph2\(^{-/-}\) littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability.},
  language  = {en}
}