Modeling Autism and Fragile X behavior in rodents

This week Dr. Richard Paylor of Baylor College of Medicine spoke at the Jackson Laboratory about his research on mouse and rat models for autism spectrum disorder (ASD). ASD spans a range of disorders in which the patient displays at minimum defects in reciprocal social interaction, impaired communication and  repetitive behaviors.

With the growing prevalence of ASD (1 in 110), research has focused on identifying its underlying genetic factors. Monozygotic twin studies have shown a 60%-90% occurrence indicating a genetic influence. However, no single causative gene has been identified.

In addition to ASD, several syndromes include ASD-like behavior. 30% to 50% of patients with Fragile X syndrome display autistic behaviors. This syndrome is caused by a triplet nucleotide repeat expansion in the gene FMR1. The symptoms and severity of this syndrome are highly variable.

A mouse model for Fragile X syndrome was created in which the Fmr1 gene was knocked-out. These mice exhibit reduced social dominance, altered social interaction dependent on context and subject familiarity, and altered repetitive behaviors. Dr. Paylor found that the autistic behaviors observed in these mice were highly dependent on strain background. On some backgrounds, Fmir1 knock-out mice exhibit increased marble burying (a measure of repetitive behavior) while on others they do not. While Fmr1 mutations may contribute to ASD, the extent will depend on the other genes being expressed.

Zinc finger endonucleases (ZFNs) are becoming a popular means for generating gene knock-outs in organisms, like the rat, in which standard knock-out technology are not efficient. Rats also offer some advantages over mice in that their physiology more closely resembles that of humans and their behaviors are easier to model than mice.

Dr. Paylor and his colleagues have generated several rat knock-out models using ZFNs targeting genes thought to be involved in ASD and Fragile-X and are studying them to compare their results to those obtained in mice.

While some rodent models in mice and rats exhibit ASD and Frigile-X behaviors observed in people, background variability and the contribution of unknown factors makes the study of these disorders as complicated in rodents as in people. These rodent models may prove vital in identifying the factors that contribute the variability of symptoms observed in people.