Fakultät für Biologie
Refine
Has Fulltext
- yes (22)
Is part of the Bibliography
- yes (22)
Document Type
- Doctoral Thesis (22)
Keywords
- Epigenetik (2)
- ADHD (1)
- Alzheimer's disease (1)
- Alzheimerkrankheit (1)
- Angeborene Immunität (1)
- Animal model (1)
- Anthropocene (1)
- Arbeitsteilung (1)
- Aspergillus fumigatus (1)
- Aussterbedynamik (1)
- Bacterial infection (1)
- Bakteriophagen (1)
- Biene (1)
- Biofilm (1)
- CNBP (1)
- Cataglyphis (1)
- Ceramide (1)
- Chlamydia trachomatis (1)
- Craniosynostosis (1)
- DG diacyglycerol (1)
- Danio rerio (1)
- Dispersal (1)
- E. coli Nissle 1917 (1)
- EHEC (1)
- Enterohemorrhagic Escherichia coli (1)
- Entwicklung (1)
- Evolution (1)
- Expansion microscopy (1)
- Expansionsmikroskopie (1)
- FOXP2 (1)
- Farbensehen (1)
- Fluoreszenzmikroskopie (1)
- Folliculin (1)
- GAD1 (1)
- GRM8 (1)
- Genetic etiology (1)
- Genetik (1)
- Genexpression (1)
- Genmutation (1)
- Gonococcal invasion (1)
- Himmelskompass (1)
- Hochauflösungsmikroskopie (1)
- Homing (1)
- Host defense (1)
- Host-pathogen interaction (1)
- Hyperactivity (1)
- Immunologie (1)
- Immunotherapy (1)
- Immunsuppression (1)
- Individual based model (IBM) (1)
- Innate immunity (1)
- Integrin (1)
- Intracellular bacteria (1)
- Intrazelluläre Bakterien (1)
- Komplexauge (1)
- Kraniosynostose (1)
- Lambdoide Prophagen (1)
- Locomotor activity (1)
- MAX (1)
- MYCN (1)
- Marine sponge-derived actinomycetes (1)
- Marine sponges (1)
- Maus (1)
- Mitochondria (1)
- Mitochondrien (1)
- Mitochondrium (1)
- Model Organism (1)
- Modellorganismus (1)
- Modellsystem (1)
- ModulationTregs (1)
- Mutation (1)
- Myeloid-derived suppressor cells (1)
- Neisseria gonorrhoeae (1)
- Nephroblastom (1)
- Netzhaut (1)
- Neuroepigenomics (1)
- Neuroethologie (1)
- Neuromodulation (1)
- Neuronale Plastizität (1)
- Neuropeptide (1)
- Neuropeptidom (1)
- Neutrophils (1)
- PE Phosphoethanolamine (1)
- Paternal age and BMI effects (1)
- Pflanzenaussterben (1)
- Pharmaceutische Biologie (1)
- Probiotikum (1)
- Protein interactor (1)
- RNA binding potein CNBP (1)
- Riesensynapsen (1)
- STD patients (1)
- Shigella flexneri (1)
- Soziale Insekten (1)
- Spatial heterogeneity (1)
- Spatiotemporal analysis (1)
- Staphylococci (1)
- Streptomyces (1)
- Stress (1)
- Superresolution microscopy (1)
- Temporal heterogeneity (1)
- Theoretical Ecology (1)
- Thigmotaxis (1)
- VLA-1 (1)
- Verhaltensplastizität (1)
- Wilms Tumor (1)
- Xiphophorus Melanom (1)
- Zebrafish (1)
- autophagocytose (1)
- autophagy (1)
- bees (1)
- chlamydia trachomatis (1)
- circadian clock (1)
- color vision (1)
- compound eyes (1)
- extinction dynamics (1)
- insects (1)
- lambdoid prophage (1)
- mechanistische Modellierung (1)
- metabolic modelling (1)
- metabolic theory of ecology (1)
- metatranscriptome (1)
- neurobiology (1)
- polarized epithelium (1)
- probiotica (1)
- protease (1)
- rapid evolution (1)
- retinal development (1)
- schnelle Evolution (1)
- stx-Phagen (1)
- stx-phages (1)
- transient dynamics (1)
Institute
- Graduate School of Life Sciences (22) (remove)
Sonstige beteiligte Institutionen
Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder described in psychiatry today. ADHD arises during early childhood and is characterized by an age-inappropriate level of inattention, hyperactivity, impulsivity, and partially emotional dysregulation. Besides, substantial psychiatric comorbidity further broadens the symptomatic spectrum. Despite advances in ADHD research by genetic- and imaging studies, the etiopathogenesis of ADHD remains largely unclear. Twin studies suggest a heritability of 70-80 % that, based on genome-wide investigations, is assumed to be polygenic and a mixed composite of small and large, common and rare genetic variants. In recent years the number of genetic risk candidates is continuously increased. However, for most, a biological link to neuropathology and symptomatology of the patient is still missing. Uncovering this link is vital for a better understanding of the disorder, the identification of new treatment targets, and therefore the development of a more targeted and possibly personalized therapy.
The present thesis addresses the issue for the ADHD risk candidates GRM8, FOXP2, and GAD1. By establishing loss of function zebrafish models, using CRISPR/Cas9 derived mutagenesis and antisense oligonucleotides, and studying them for morphological, functional, and behavioral alterations, it provides novel insights into the candidate's contribution to neuropathology and ADHD associated phenotypes. Using locomotor activity as behavioral read-out, the present work identified a genetic and functional implication of Grm8a, Grm8b, Foxp2, and Gad1b in ADHD associated hyperactivity. Further, it provides substantial evidence that the function of Grm8a, Grm8b, Foxp2, and Gad1b in activity regulation involves GABAergic signaling. Preliminary indications suggest that the three candidates interfere with GABAergic signaling in the ventral forebrain/striatum. However, according to present and previous data, via different biological mechanisms such as GABA synthesis, transmitter release regulation, synapse formation and/or transcriptional regulation of synaptic components. Intriguingly, this work further demonstrates that the activity regulating circuit, affected upon Foxp2 and Gad1b loss of function, is involved in the therapeutic effect mechanism of methylphenidate. Altogether, the present thesis identified altered GABAergic signaling in activity regulating circuits in, presumably, the ventral forebrain as neuropathological underpinning of ADHD associated hyperactivity. Further, it demonstrates altered GABAergic signaling as mechanistic link between the genetic disruption of Grm8a, Grm8b, Foxp2, and Gad1b and ADHD symptomatology like hyperactivity. Thus, this thesis highlights GABAergic signaling in activity regulating circuits and, in this context, Grm8a, Grm8b, Foxp2, and Gad1b as exciting targets for future investigations on ADHD etiopathogenesis and the development of novel therapeutic interventions for ADHD related hyperactivity. Additionally, thigmotaxis measurements suggest Grm8a, Grm8b, and Gad1b as interesting candidates for prospective studies on comorbid anxiety in ADHD. Furthermore, expression analysis in foxp2 mutants demonstrates Foxp2 as regulator of ADHD associated gene sets and neurodevelopmental disorder (NDD) overarching genetic and functional networks with possible implications for ADHD polygenicity and comorbidity. Finally, with the characterization of gene expression patterns and the generation and validation of genetic zebrafish models for Grm8a, Grm8b, Foxp2, and Gad1b, the present thesis laid the groundwork for future research efforts, for instance, the identification of the functional circuit(s) and biological mechanism(s) by which Grm8a, Grm8b, Foxp2, and Gad1b loss of function interfere with GABAergic signaling and ultimately induce hyperactivity.