TY - THES A1 - Post, Antonia T1 - Snap25 heterozygous knockout mice as a potential model for attention deficit/hyperactivity disorder (ADHD) T1 - Heterozygote Snap25 Knockout-Mäuse als Modell für Aufmerksamkeitsdefizit- / Hyperaktivitätssyndrom (ADHS) N2 - SNAP25 (Synaptosomal-Associated Protein of 25 kDa; part of the SNARE complex) is involved in the docking and fusion of synaptic vesicles in presynaptic neurons necessary for the regulation of neurotransmitter release, as well as in axonal growth and synaptic plasticity. In humans, different single nucleotide polymorphisms of SNAP25 have repeatedly been associated with attention deficit/hyperactivity disorder (ADHD). Thus, in this study heterozygous Snap25 knockout mice were investigated as a model of ADHD. Heterozygous (+/-) Snap25 knockout mice as well as their wild-type (+/+) littermates were reared under control conditions or underwent a Maternal Separation (MS) procedure. Starting at the age of 2 months, mice were tested for locomotor activity in a repeated long-term Open Field (OF) task, for attention deficits and impulsive behavior in the 5 Choice Serial Reaction Time Task (5CSRTT), for anxiety-like behavior in the Light-Dark Box (LDB) and for depression-like behavior in the Porsolt Forced Swim Test (FST). The brains of these mice were subsequently tested for the expression of several ADHD related genes in a quantitative Real-Time PCR (qRT-PCR) study. Another group of female mice (+/+; +/-) underwent a one hour OF test after oral administration of 45 mg/kg Methylphenidate (MPH) or placebo. To find an optimized dosage for this MPH challenge, a pilot study was performed. Wild-type C57BL/6 mice were tested in a long-term OF with several dosages of MPH both intraperitoneally (i.p.) and orally. The brains of these animals were afterwards investigated for neurotransmitter concentrations. In this pilot study the dosages of MPH that were similarly behaviorally effective without causing symptoms of overdosing were 7.5-15 mg/kg intraperitoneally and 30-60 mg/kg orally. However, even though it was possible to find intraperitoneal and oral doses that correlate behaviorally, the neurochemistry was mostly different. In the study on Snap25-deficient mice, unstressed controls showed a hyperactive phenotype in the second of two long-term OF sessions (60 min) spaced three weeks apart. Considering all groups, there was a significant interaction of stress and genotype in the second session, with animals subjected to MS being overall hyperactive with no genotype differences. In the training phase of the 5CSRTT only effects of stress were found, with MS animals finding and consuming fewer rewards. In the single test trial, several genotype effects became apparent, with tendencies for the number of correct nose pokes and the number of rewards eaten, and a significant effect for the number of rewards eaten directly after the correct response. In all of these variables +/- mice performed worse than their wild-type littermates. In the LDB +/- mice entered the lit compartment of the arena earlier than the controls, thus showing attenuated anxiety-like behavior. Regarding depressive-like behavior in the FST, male +/- mice spent significantly less time struggling than male +/+ mice. In the gene expression study, +/- mice had lower expression levels of Maoa and Comt, and higher expression levels of Nos1 than wild-types. Finally, the locomotor activity response to MPH was exaggerated in +/- mice as compared to controls. Heterozygous Snap25 knockout mice show some of the behavioral characteristics of ADHD, as for example a mild hyperactivity in a familiar environment, difficulties in the correct execution of a given task and even some behavior that can be interpreted as delay aversion. Additionally, expression levels of three ADHD related genes were changed in these animals. Although the exaggerated locomotor activity response to MPH is not to be expected of an ADHD model, the difference in the response between +/+ and +/- mice nonetheless implicates a potential dysfunction of the brain dopaminergic system. N2 - SNAP25 (Synaptosomal assoziiertes Protein, 25 kDa; Teil des SNARE Komplexes) ist an der Fusion von synaptischen Vesikeln mit der präsynaptischen Zellmembran beteiligt, und somit notwendig für die Regulation der Neurotransmitter-Ausschüttung. Außerdem wird eine wichtige Funktion bei dem Wachstum von Axonen und synaptischer Plastizität diskutiert. In Humanstudien wurden wiederholt verschiedene Einzelnukleotid-polymorphismen von SNAP25 mit Aufmerksamkeitsdefizit- / Hyperaktivitätssyndrom (ADHS) assoziiert. In der vorliegenden Studie wurden heterozygote Snap25 knockout Mäuse als Modell für ADHS untersucht. Heterozygote (+/-) Snap25 knockout Mäuse und ihre wildtypischen Wurfgeschwister wurden unter Kontrollbedingungen großgezogen oder einer maternalen Separation (MS) unterzogen. Beginnend im Alter von etwa 2 Monaten wurden diese Mäuse verschiedenen Verhaltenstests unterzogen: in einem wiederholten Langzeit-Open-Field (OF) Test wurde Aktivität untersucht, Aufmerksamkeitsdefizite und Impulsivität mit dem 5 Choice Serial Reaction Time Task (5CSRTT), angst-ähnliches Verhalten in der Light-Dark Box (LDB) und depressions-ähnliches Verhalten im Porsolt Forced Swim Test (FST). Die Gehirne dieser Mäuse wurden anschließend auf die Expression verschiedener ADHS bezogener Gene in einer quantitativen Real-Time-PCR (qRT-PCR) untersucht. Eine zusätzliche Gruppe weiblicher Mäuse (+/+; +/-) durchlief einen einstündigen OF Test nach oraler Gabe von 45 mg/kg Methylphenidat (MPH) oder Placebo. Um eine optimale Dosierung für MPH in diesem Experiment zu finden, wurde eine Pilotstudie durchgeführt. Hierbei wurden wildtypische C57/BL6 Mäuse in einem Langzeit OF Test mit Gabe unterschiedlicher Dosierungen von MPH, sowohl oral als auch intraperitoneal (i.p.), untersucht. Im Anschluss wurden die Gehirne dieser Tiere auf Neurotransmitter-konzentration geprüft. Diese Pilotstudie ergab als optimale Dosierungen von MPH auf Verhaltensebene 7.5-15 mg/kg i.p. und 30-60 mg/kg oral. Allerdings waren die neurochemischen Effekte der beiden unterschiedlichen Applikationsarten größtenteils verschieden. In der Snap25 Studie zeigten ungestresste Kontroll-Tiere einen leicht hyperaktiven Phänotyp in dem zweiten von zwei Langzeit-Open-Field Tests (60 min) im Abstand von 3 Wochen. Bei Betrachtung aller Gruppen ergab sich auch eine signifikante Interaktion von Stress und Genotyp in der zweiten Testung, und zwar dahingehend, dass MS Tiere grundsätzlich aktiveres Verhalten zeigten, ohne Genotypen-Unterschiede. In der Anfangsphase des 5CSRTT lagen nur signifikante Haupteffekte für Stress vor, gestresste Tiere hatten größere Probleme im Meistern der Aufgabe als Wildtypen. Erst im sogenannten Test-Trial am Ende der Versuchsreihe ergaben sich signifikante Haupteffekte für den Genotyp. Heterozygote Snap25 knockout Mäuse zeigten beispielsweise weniger korrekte Reaktionen und konsumierten auch weniger Belohnungspellets direkt im Anschluss an eine korrekte Reaktion als Wildtypen. In der LDB brauchten +/- Mäuse wiederum weniger Zeit als Wildtypen, um den erleuchteten Teil der Arena zu betreten, und zeigten dadurch ein reduziertes Angst-ähnliches Verhalten. Im Gegensatz dazu ergab sich ein erhöht Depressions-ähnliches Verhalten für männliche heterozygote Snap25 knockout Mäuse im FST. Auf der Genexpressions-Ebene hatten +/- Mäuse niedrigere Expressionslevels von Maoa und Comt und höhere Expressionslevels von Nos1 als Wildtypen. Abschließend zeigte sich eine erhöhte Reaktion auf MPH bei heterozygoten Mäusen. Zusammenfassend zeigen heterozygote Snap25 knockout Mäuse einige Charakteristika von ADHS auf Verhaltensebene, wie zum Beispiel eine leichte Hyperaktivität in bekannter Umgebung, Schwierigkeiten im Erlernen einer gestellten Aufgabe und sogar Verhaltensweisen, die auf eine Abneigung gegenüber Verzögerungen hindeuten. Zusätzlich kommt es aufgrund des Knockouts zu veränderten Expressionslevels verschiedener ADHS assoziierter Gene. Auch wenn die erhöhte Verhaltensreaktion von +/- Mäusen auf MPH nicht die erwartete Reaktion eines ADHS Modells darstellt, deutet sie dennoch auf ein Ungleichgewicht des dopaminergen Systems im Gehirn hin, das bei ADHS eine wichtige Rolle spielt. KW - Aufmerksamkeitsdefizit-Syndrom KW - SNAP-Rezeptor KW - Tiermodell KW - Verhalten KW - Genexpression KW - Animal model KW - Snap25 KW - Attention deficit / hyperactivity disorder Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122899 ER - TY - JOUR A1 - Frey, Anna A1 - Popp, Sandy A1 - Post, Antonia A1 - Langer, Simon A1 - Lehmann, Marc A1 - Hofmann, Ulrich A1 - Siren, Anna-Leena A1 - Hommers, Leif A1 - Schmitt, Angelika A1 - Strekalova, Tatyana A1 - Ertl, Georg A1 - Lesch, Klaus-Peter A1 - Frantz, Stefan T1 - Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain JF - Frontiers in Behavioral Neuroscience N2 - Background: Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). Methods and Results: In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. Conclusions: After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression. KW - chronic heart failure KW - myocardial infarction KW - anxiety KW - depression KW - mice Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118234 SN - 1662-5153 VL - 8 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 -