TY - JOUR A1 - Ziegler, Georg C. A1 - Almos, Peter A1 - McNeill, Rhiannon V. A1 - Jansch, Charline A1 - Lesch, Klaus‐Peter T1 - Cellular effects and clinical implications of SLC2A3 copy number variation JF - Journal of Cellular Physiology N2 - SLC2A3 encodes the predominantly neuronal glucose transporter 3 (GLUT3), which facilitates diffusion of glucose across plasma membranes. The human brain depends on a steady glucose supply for ATP generation, which consequently fuels critical biochemical processes, such as axonal transport and neurotransmitter release. Besides its role in the central nervous system, GLUT3 is also expressed in nonneural organs, such as the heart and white blood cells, where it is equally involved in energy metabolism. In cancer cells, GLUT3 overexpression contributes to the Warburg effect by answering the cell's increased glycolytic demands. The SLC2A3 gene locus at chromosome 12p13.31 is unstable and prone to non‐allelic homologous recombination events, generating multiple copy number variants (CNVs) of SLC2A3 which account for alterations in SLC2A3 expression. Recent associations of SLC2A3 CNVs with different clinical phenotypes warrant investigation of the potential influence of these structural variants on pathomechanisms of neuropsychiatric, cardiovascular, and immune diseases. In this review, we accumulate and discuss the evidence how SLC2A3 gene dosage may exert diverse protective or detrimental effects depending on the pathological condition. Cellular states which lead to increased energetic demand, such as organ development, proliferation, and cellular degeneration, appear particularly susceptible to alterations in SLC2A3 copy number. We conclude that better understanding of the impact of SLC2A3 variation on disease etiology may potentially provide novel therapeutic approaches specifically targeting this GLUT. KW - copy number variation KW - energy metabolism KW - glucose transporter KW - GLUT3 KW - neurodegeneration KW - neurodevelopment KW - SLC2A3 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218009 VL - 235 IS - 12 SP - 9021 EP - 9036 ER - 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 - Ferero, Andrea A1 - Rivero, Olga A1 - Wäldchen, Sina A1 - Ku, Hsing-Ping A1 - Kiser, Dominik P. A1 - Gärtner, Yvonne A1 - Pennington, Laura S. A1 - Waider, Jonas A1 - Gaspar, Patricia A1 - Jansch, Charline A1 - Edenhofer, Frank A1 - Resink, Thérèse J. A1 - Blum, Robert A1 - Sauer, Markus A1 - Lesch, Klaus-Peter T1 - Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain JF - Frontiers in Cellular Neuroscience N2 - 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. KW - serotonin KW - cadherin-13 (CDH13) KW - T-cadherin KW - neurodevelopment KW - psychiatric disorders KW - radial glia KW - dorsal raphe KW - prefrontal cortex Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170313 VL - 11 IS - 307 ER - TY - JOUR A1 - Kästner, Niklas A1 - Richter, S. Helene A1 - Urbanik, Sarah A1 - Kunert, Joachim A1 - Waider, Jonas A1 - Lesch, Klaus-Peter A1 - Kaiser, Sylvia A1 - Sachser, Norbert T1 - Brain serotonin deficiency affects female aggression JF - Scientific Reports N2 - The neurotransmitter serotonin plays a key role in the control of aggressive behaviour. While so far most studies have investigated variation in serotonin levels, a recently created tryptophan hydroxylase 2 (Tph2) knockout mouse model allows studying effects of complete brain serotonin deficiency. First studies revealed increased aggressiveness in homozygous Tph2 knockout mice in the context of a resident-intruder paradigm. Focussing on females, this study aimed to elucidate effects of serotonin deficiency on aggressive and non-aggressive social behaviours not in a test situation but a natural setting. For this purpose, female Tph2 wildtype (n = 40) and homozygous knockout mice (n = 40) were housed with a same-sex conspecific of either the same or the other genotype in large terraria. The main findings were: knockout females displayed untypically high levels of aggressive behaviour even after several days of co-housing. Notably, in response to aggressive knockout partners, they showed increased levels of defensive behaviours. While most studies on aggression in rodents have focussed on males, this study suggests a significant involvement of serotonin also in the control of female aggression. Future research will show, whether the observed behavioural effects are directly caused by the lack of serotonin or by potential compensatory mechanisms. KW - animal behaviour KW - genetics of the nervous system KW - social behaviour Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325386 VL - 9 ER - TY - JOUR A1 - Bodden, Carina A1 - Richter, S. Helene A1 - Schreiber, Rebecca S. A1 - Kloke, Vanessa A1 - Gerß, Joachim A1 - Palme, Rupert A1 - Lesch, Klaus-Peter A1 - Lewejohann, Lars A1 - Kaiser, Sylvia A1 - Sachser, Norbert T1 - Benefits of adversity?! How life history affects the behavioral profile of mice varying in serotonin transporter genotype JF - Frontiers in Behavioral Neuroscience N2 - Behavioral profiles are influenced by both positive and negative experiences as well as the genetic disposition. Traditionally, accumulating adversity over lifetime is considered to predict increased anxiety like behavior ("allostatic load"). The alternative "mismatch hypothesis" suggests increased levels of anxiety if the early environment differs from the later-life environment. Thus, there is a need for a whole-life history approach to gain a deeper understanding of how behavioral profiles are shaped. The aim of this study was to elucidate the effects of life history on the behavioral profile of mice varying in serotonin transporter (5-HIT) genotype, an established mouse model of increased anxiety-like behavior. For this purpose, mice grew up under either adverse or beneficial conditions during early phases of life. In adulthood, they were further subdivided so as to face a situation that either matched or mismatched the condition experienced so far, resulting in four different life histories. Subsequently, mice were tested for their anxiety-like and exploratory behavior. The main results were: (1) Life history profoundly modulated the behavioral profile. Surprisingly, mice that experienced early beneficial and later escapable adverse conditions showed less anxiety-like and more exploratory behavior compared to mice of other life histories. (2) Genotype significantly influenced the behavioral profile, with homozygous 5-HTT knockout mice displaying highest levels of anxiety-like and lowest levels of exploratory behavior. Our findings concerning life history indicate that the absence of adversity does not necessarily cause lower levels of anxiety than accumulating adversity. Rather, some adversity may be beneficial, particularly when following positive events. Altogether, we conclude that for an understanding of behavioral profiles, it is not sufficient to look at experiences during single phases of life, but the whole life history has to be considered. KW - anxiety-like behavior KW - maternal care KW - dangerous world KW - animal behavior KW - match-mismatch KW - chronic social stress KW - elevated plus-maze KW - 5-HTT KW - life history KW - predictive adaptive response hypothesis KW - developmental plasticity KW - knockout mice KW - environmental enrichment KW - allostatic load Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143723 VL - 9 IS - 47 ER - TY - JOUR A1 - Veniaminova, Ekaterina A1 - Cespuglio, Raymond A1 - Cheung, Chi Wai A1 - Umriukhin, Alexei A1 - Markova, Nataliia A1 - Shevtsova, Elena A1 - Lesch, Klaus-Peter A1 - Anthony, Daniel C. A1 - Strekalova, Tatyana T1 - Autism-like behaviours and memory deficits result from a Western Diet in mice JF - Neural Plasticity N2 - Nonalcoholic fatty liver disease, induced by a Western diet (WD), evokes central and peripheral inflammation that is accompanied by altered emotionality. These changes can be associated with abnormalities in social behaviour, hippocampus-dependent cognitive functions, and metabolism. Female C57BL/6J mice were fed with a regular chow or with a WD containing 0.2% of cholesterol and 21% of saturated fat for three weeks. WD-treated mice exhibited increased social avoidance, crawl-over and digging behaviours, decreased body-body contacts, and hyperlocomotion. The WD-fed group also displayed deficits in hippocampal-dependent performance such as contextual memory in a fear conditioning and pellet displacement paradigms. A reduction in glucose tolerance and elevated levels of serum cholesterol and leptin were also associated with the WD. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1a) mRNA, a marker of mitochondrial activity, was decreased in the prefrontal cortex, hippocampus, hypothalamus, and dorsal raphe, suggesting suppressed brain mitochondrial functions, but not in the liver. This is the first report to show that a WD can profoundly suppress social interactions and induce dominant-like behaviours in naïve adult mice. The spectrum of behaviours that were found to be induced are reminiscent of symptoms associated with autism, and, if paralleled in humans, suggest that a WD might exacerbate autism spectrum disorder. KW - diet KW - autism-like behavior KW - mice Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158211 ER -