From zebrafish to patients: Using zebrafish to uncover the genetic and neural basis of aggression in neurodevelopmental disorders

Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental condition characterized by repetitive behaviours and difficulties in social interaction. It is a very complex disorder, understood to occur due to a combination of environmental and genetic factors affecting synapses. 25% of ASD cases have been reported to be attributed to genetic influence. 2-out-of-3 autistic individuals show increased aggression, having detrimental effects on the quality of life of both affected individuals and their families. For children with ASD, aggressive behaviour is associated with adverse outcomes in social relationships, such as the risk of being victimised or physical intervention required and placement in restrictive settings. There are also adverse outcomes for caregivers of individuals with ASD, with negative impacts on day-to-day life from higher stress levels, lack of support and financial strain.

Despite the worldwide incidence increase of autism, and aggression being one of the most reported challenges faced by caregivers of autistic individuals, we lack effective treatments. Available treatments have borrowed from successful treatment of other neuropsychiatric disorders. This is because of our poor understanding of underlying mechanisms of how these mutations perturb developmental trajectories and wiring of the brain.

by combining existing mouse data with the zebrafish studies outlined here, will be employed to address the following:

The impact of NRXN1 knockout and Nlgn3A451C mutation on:

challenging behaviours (aggression/anxiety)

axonal growth/synapse formation

E/I balance

whole brain activity

Use of zebrafish mutants for pharmacological screening of novel compounds which may improve ASD-associated aggressive behaviour