United Kingdom Research and Innovation, Medical Research Council and King's College London

New autism mouse model


New autism mouse model

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental disorders, affecting more than 1/100 people. ASD is extremely diverse, complicating clinical studies to understand the underlying neurobiology. For instance, whilst the majority of functional imaging studies on idiopathic ASD patients tend to support a view of reduced long-range functional connectivity, some studies suggest the opposite. Recent gene sequencing efforts have provided insights into the genetic heterogeneity of ASD and provide an opportunity to understand how ASD subtypes with distinct genetic causes differ with respect to brain development and function.

A new study by Albert Basson’s laboratory from the Centre for Craniofacial and Regenerative Biology and the MRC Centre for Neurodevelopmental Disorders, with collaborators from King’s, Italy and Canada, published in the journal Cerebral Cortex, provide important new insights into these questions. They generated a new mouse model to study how one of the strongest ASD genes identified to date affect brain development and function. This gene, CHD8, encodes a factor that modulates the expression of neurodevelopmental genes by regulating the structure of chromatin. CHD8 forms part of a new group of chromatin remodeling factor genes only recently associated with ASD. How mutation in these factors disrupt brain development and cause ASD is not known. By studying these mice the researchers found that many other ASD-associated genes were dysregulated in the early postnatal cortex. Many of these genes regulate the formation of neuronal connections (synapses) and axon guidance, the process whereby neurons find their targets over long distances. Intriguingly, by performing resting state functional magnetic resonance imaging, a technique often employed to assess functional, long-range connectivity in the human brain, the researchers found evidence that specific brain regions show increased functional connectivity. This finding contrasts with previous studies on other ASD mouse models that have all so far found evidence of reduced functional connectivity. The realization that different types of ASD can be distinguished by different, and even opposite results in functional imaging, has important implications for both diagnosis and treatment of ASD-associated conditions. Functional MRI could be used to identify patients with different kinds of ASD, and the expectation is that patients that differ this way may also respond differently to medication.

In addition to the functional imaging studies, the researchers also compared the craniofacial and structural brain phenotypes of Chd8 mutant mice with normal controls. They found evidence for specific craniofacial changes and brain overgrowth, both phenotypes that characterize patients with CHD8 mutations. Surprisingly, these mice did not show behaviours typically associated with autism – avoidance of social interactions, repetitive and perseverative behaviours. Instead, these mice showed evidence for a heightened interest in social cues. Albert Basson, senior author of the study said: “So far, these mice have been full of surprises. We expected them to exhibit strong “autism-like” behaviours, which they didn’t. They showed functional over-connectivity, rather than under-connectivity. Understanding the basis of these observations will provide important insights into ASD aetiology and we are continuing our work on this mouse model to unravel and understand these interesting findings”.

The study is one of several recent studies describing Chd8 mouse models. Although the study by the Basson group is the first to find evidence for abnormal functional connectivity, other mouse models also found increased brain size and dysregulation of other ASD genes.

This study was supported by grants from the Medical Research Council (Albert Basson, Cathy Fernandes), the Simons Foundation (Albert Basson, Alessandro Gozzi), Ontario Brain Institute’s POND program (Jason Lerch), BBSRC (Philippa Francis-West), PhD studentships from the King’s Bioscience Institute and the Guy’s and St Thomas’ Charity Prize PhD Program in Biomedical and Translational Science (Shaun Hurley and Rob Ellingford), and a NARSAD Independent Investigator Grant from the Brain and Behavior Research Foundation (Alessandro Gozzi).

Paper reference: Suetterlin, P., Hurley, S., Mohan, C., Riegman, K.L.H., Pagani, M., Caruso, A., Ellegood, J., Galbusera, A., Crespo-Enriquez, I., Michetti, C., Yee, Y., Ellingford, R., Brock, O., Delogu, A., Francis-West, P., Lerch, J.P., Scattoni, M.L., Fernandes, C. & Basson, M.A. (2018). Altered neocortical gene expression, brain overgrowth and functional over-connectivity in Chd8 haploinsufficient mice . Cereb. Cortex.

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