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

Abstract

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 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.

GRM7 deficiency, from excitotoxicity and neuroinflammation to neurodegeneration: Systematic review of GRM7 deficient patients

“…Thus, heterozygous carriers remain largely asymptomatic. It is posited that heterozygous GRM7 mutations may cause disease only in the presence of other confounding genetic or environmental factors and as consequence of mGluR isoform mutation variation ( Lüffe et al, 2022 ) ( Fig. 3 ).…”

Population genomic analysis of the greater amberjack (Seriola dumerili) in the Mediterranean and the Northeast Atlantic, based on SNPs, microsatellites, and mitochondrial DNA sequences

“…Subsequently, here we focused on the genes with better established documentation. Most of them were involved in aspects of embryonic development, fin morphogenesis, notochord development in fish (pdgfa, frem2b, col27a1) (73-75), normal brain function and behavioral phenotypes in fish (grm8, nrxn2) (76,77), and potential role in immune response in human tissues (78). Finally, we identified tead1a/TEF-1A, which is associated with a cold-acclimation mechanism in medaka [Oryzias latipes; (79)], and sec23ip, which plays a role in spermiogenesis in mice (80).…”