Lecture 14 - Modelling Neurodevelopmental Disorders

Question 1

What is ASD?

Answer 1

A lifelong developmental disorder characterised by persistent deficits in social communication and interaction.
Restricted, repetitive patterns of behaviour, interests or activities.
No biomarker or cure.
Autistic traits are highly heritable.

Question 2

Why do we need preclinical models of ASD?

Answer 2

No single aetiology for ASD - complex interplay between genetics and environment.
Lack of pharmacological and neurobiological solutions and lack of understanding of ASD neurobiology.

Question 3

What 3 things do we need for a good animal model?

Answer 3

Construct validity
Face validity
Predictive validity

Question 4

What is construct validity?

Answer 4

Biological cause itself.
Example - Rett syndrome caused by one gene mutation (MECP2) so if this is induced in an animal model there is high construct validity.

Question 5

What is face validity?

Answer 5

Behaviours and how closely observable syndromes or outcomes in the animal model match those in human patients.

Question 6

What is predictive validity?

Answer 6

Seeing how well treatments work in animals compared to humans.

Question 7

What is the key validity criteria for construct validity in animal models?

Answer 7

Phenotype emerges spontaneously or is induce through natural presence or gene-editing of highly penetrant autism susceptibility genes.
Must emerge early in development and persist into adulthood.
Better results achieved with decreasing phylogenetic distance between model organism and humans so there is greater homology in relevant genes, pathways and circuits.

Question 8

What is the key validity criteria for face validity in animal models?

Answer 8

Presence of complex social interaction impairments and repetitive behaviours.
Highly social species with vision as its primary sensory modality.

Question 9

What is the key validity criteria for predictive validity in animal models?

Answer 9

Medications should safely target core ASD features.
Should ameliorate social impairments and/or diminish repetitive behaviours with minimal side effects in both the animal model and humans.

Question 10

Why are nonhuman primates used to study ASD and not rodents?

Answer 10

Closely related to humans.
Bridges the gap in knowledge that can’t be done using humans.
Live in advanced social groups with diverse ways of communications including expression.
Rodents do not have a PFC which is important in ASD phenotypes so they have less face validity.
Nonhuman primate research is limited due to ethical considerations.