Loss-of-Function Models of the Metabotropic Glutamate Receptor Genes Grm8a and Grm8b Display Distinct Behavioral Phenotypes in Zebrafish Larvae (Danio rerio)

Please always quote using this URN: urn:nbn:de:bvb:20-opus-277429
  • Members of the family of metabotropic glutamate receptors are involved in the pathomechanism of several disorders of the nervous system. Besides the well-investigated function of dysfunctional glutamate receptor signaling in neurodegenerative diseases, neurodevelopmental disorders (NDD), like autism spectrum disorders (ASD) and attention-deficit and hyperactivity disorder (ADHD) might also be partly caused by disturbed glutamate signaling during development. However, the underlying mechanism of the type III metabotropic glutamate receptor 8Members of the family of metabotropic glutamate receptors are involved in the pathomechanism of several disorders of the nervous system. Besides the well-investigated function of dysfunctional glutamate receptor signaling in neurodegenerative diseases, neurodevelopmental disorders (NDD), like autism spectrum disorders (ASD) and attention-deficit and hyperactivity disorder (ADHD) might also be partly caused by disturbed glutamate signaling during development. However, the underlying mechanism of the type III metabotropic glutamate receptor 8 (mGluR8 or GRM8) involvement in neurodevelopment and disease mechanism is largely unknown. Here we show that the expression pattern of the two orthologs of human GRM8, grm8a and grm8b, have evolved partially distinct expression patterns in the brain of zebrafish (Danio rerio), especially at adult stages, suggesting sub-functionalization of these two genes during evolution. Using double in situ hybridization staining in the developing brain we demonstrate that grm8a is expressed in a subset of gad1a-positive cells, pointing towards glutamatergic modulation of GABAergic signaling. Building on this result we generated loss-of-function models of both genes using CRISPR/Cas9. Both mutant lines are viable and display no obvious gross morphological phenotypes making them suitable for further analysis. Initial behavioral characterization revealed distinct phenotypes in larvae. Whereas grm8a mutant animals display reduced swimming velocity, grm8b mutant animals show increased thigmotaxis behavior, suggesting an anxiety-like phenotype. We anticipate that our two novel metabotropic glutamate receptor 8 zebrafish models may contribute to a deeper understanding of its function in normal development and its role in the pathomechanism of disorders of the central nervous system.show moreshow less

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Metadaten
Author: Teresa M. Lüffe, Moritz Bauer, Zoi Gioga, Duru Özbay, Marcel Romanos, Christina Lillesaar, Carsten Drepper
URN:urn:nbn:de:bvb:20-opus-277429
Document Type:Journal article
Faculties:Medizinische Fakultät / Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie
Language:English
Parent Title (English):Frontiers in Molecular Neuroscience
ISSN:1662-5099
Year of Completion:2022
Volume:15
Article Number:901309
Source:Frontiers in Molecular Neuroscience (2022) 15:901309. DOI:10.3389/fnmol.2022.901309
DOI:https://doi.org/10.3389/fnmol.2022.901309
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:brain development; brain disorders; excitatory/inhibitory imbalance; metabotropic glutamate (mGlu) receptor; nervous system; psychiatric disorders
Release Date:2023/04/14
Date of first Publication:2022/06/13
Open-Access-Publikationsfonds / Förderzeitraum 2022
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International