Zebrafish Modeling of Autism Spectrum Disorders, Current Status and Future Prospective

Abstract

Autism spectrum disorder (ASD) refers to a complicated range of childhood neurodevelopmental disorders which can occur via genetic or non-genetic factors. Clinically, ASD is associated with problems in relationships, social interactions, and behaviors that pose many challenges for children with ASD and their families. Due to the complexity, heterogeneity, and association of symptoms with some neuropsychiatric disorders such as ADHD, anxiety, and sleep disorders, clinical trials have not yielded reliable results and there still remain challenges in drug discovery and development pipeline for ASD patients. One of the main steps in promoting lead compounds to the suitable drug for commercialization is preclinical animal testing, in which the efficacy and toxicity of candidate drugs are examined in vivo. In recent years, zebrafish have been able to attract the attention of many researchers in the field of neurological disorders such as ASD due to their outstanding features. The presence of orthologous genes for ASD modeling, the anatomical similarities of parts of the brain, and similar neurotransmitter systems between zebrafish and humans are some of the main reasons why scientists draw attention to zebrafish as a prominent animal model in preclinical studies to discover highly effective treatment approaches for the ASD through genetic and non-genetic modeling methods.

Keywords: Danio rerio; animal modeling; autism spectrum disorders; drug development; drug discovery; zebrafish.

FIGURE 1

Genes involved in alterations of signaling pathways in ASD (26, 34).

FIGURE 2

Some strategies to investigate the ASD-like behaviors in zebrafish. (1) In order to assess social preferences, a live zebrafish or robot or photo or zebrafish video is used in an adjacent tank or multi-chamber tank to show the conspecific fish. In this experiment, the social preference behavior is examined by measuring the distance of the fish from the conspecific fish (photo, video, or robot) in the adjacent tank. (2) In order to investigate shoal behavior in the zebrafish, the studied model is placed among a group of conspecific fish inside a tank. In this experiment, the incidence of shoal behavior is determined based on the average distance between the fish in a tank. (3) In order to investigate behavioral avoidance, one of the chamber of the tank becomes dark, which is instinctively more desirable for zebrafish than a brighter environment. However, the presence of the electric shock in a dark environment is considered a risk factor for zebrafish. Hence the conflict between swimming into the dark environment instinctively and avoiding electric shock can be used to investigate behavioral avoidance. (4) In order to assess the aggression behavior, a mirror is applied inside the tank of the zebrafish. (5) The locomotor behavior can be assessed by tracking the position of zebrafish in 3D space and swim path characteristics (22).