Characterization of the role of the adgrl3.1 gene in zebrafish and its interactions with environment

Abstract

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by the clinical manifestation of attention deficits and/or hyperactivity. The Adhesion G Protein-Coupled Receptor L3 (ADGRL3) gene is strongly linked to ADHD susceptibility, and is homologous to the adgrl3.1 gene in zebrafish. The aim of this thesis was to investigate the behavioural phenotypes of adgrl3.1 knockout zebrafish and associated interactions with environmental factors. We first investigated the behavioural phenotypes of adult adgrl3.1 knockouts focusing on impulsivity, attention, decision making, locomotion, anxiety, memory, and cognition. Here, we found that adgrl3.1 knockouts show increased locomotion, impulsivity, attention deficits, anxiety, abnormal repetitive behaviour, and deficits in cognitive flexibility. We discovered a potentially novel mechanism that may underlie these behaviours, characterized by upregulation of the noradrenergic transporter, together with lower levels of DOPAC/DA in the telencephalon. The behavioural phenotype of adgrl3.1 knockout was reversed by pretreatment with atomoxetine (norepinephrine reuptake inhibitor) supporting our discoveries that norepinephrine has an essential role in the ADHD-like behaviours. The interactions of this gene with environment were also analysed focusing on how environmental enrichment, social isolation and early-life stress can affect ADHD-like behaviour. In conclusion, we showed that adgrl3.1 mutants can be a reliable model to study ADHD and its comorbidities in zebrafish. We have also demonstrated that environment can significantly affect adgrl3.1 altered behaviour positively or negatively, depending on context. Finally, for the first time, here we showed changes in the noradrenergic system that may contribute to the development of new combined treatments and further our understanding of the mechanisms underlying adult ADHD-like behaviour across species.

Date of Award	Nov 2021
Original language	English
Awarding Institution	University of Portsmouth
Supervisor	Matthew Parker (Supervisor)