GRM8, the role of a metabotropic glutamate receptor in ADHD

Introduction Attention-deficit-hyperactivity disorder (ADHD), the most common neurodevelopmental disorder, is characterized by an early childhood-onset and the core symptoms comprise inattention, hyperactivity and impulsivity. Profound research on the identification of potential causes revealed both environmental factors and a strong genetic component as contributors to an increased ADHD susceptibility (Biederman & Faraone, 2005) which helped to identify a number of potential risk genes (Demontis et al., 2019, Elia et al., 2015).

Methods As such, the gene for the metabotropic glutamate receptor 8 (GRM8/mGluR8), a member of the type III receptor family, was discovered. Type III mGlur receptors are G protein-coupled receptors (GPCR) that are predominantly situated at the presynapse where they are involved in regulation of transmitter release (Cartmell & Schoepp, 2000). Since a regulated release is required for balanced transmitter levels, GRM8 displays a relevant candidate with respect to molecular and functional circuits contributing to the pathophysiology of ADHD.

Results In the present study we use the well-established developmental model organism zebrafish (Danio rerio) to monitor the spatiotemporal expression of the GRM8 zebrafish paralogs grm8a and grm8b during embryonic development. Supported by different co-expression assays we show that grm8a/8b are expressed by GABAergic neurons among other cell types. In order to investigate its functional relevance we used a transient knockdown strategy and thereby reveal an influence of Grm8 on larval locomotion behavior.

Conclusion With the generation of several CRISPR/Cas9 knockout lines we have now established the basis to study the role of Grm8 in various cell populations and neuronal circuits to reveal how it may contribute to the pathophysiology of ADHD.