Autism can be a devastating condition for which no suitable treatment exists. Autism affects some of the core behavioural features an individual needs to function in society, namely social interaction and both verbal and non-verbal communication. Children affected by autism often demonstrate restricted, repetitive patterns of behaviour and interests. The number of individuals diagnosed with Autism Spectrum Disorder (ASD) has increased dramatically over the last decade and current estimates suggest that up to 1/110 of the population may be affected. The causes of autism are not known and without this knowledge, there is limited hopes of finding novel ways of treating this condition or improving the lives of autistic children. Autism is a complex genetic condition; many genetic abnormalities that can predispose a child to autism have been identified, but our knowledge on how these genetic risk factors can cause changes during brain development to result in autistic behaviour is extremely limited. Studies in autistic children have suggested that the growth of certain parts of the brain might to be altered during development. The part of the brain that appears to be affected most often is the cerebellum. The cerebellum controls movement, but also functions as an important modulator of other parts of the brain, including regions involved in social cognition and language development. It is not known how these defects in the cerebellum arise, nor is it known what the effects of cerebellar defects are on behaviours characteristic of autism. Currently, the best way to address this question directly is to study brain development and the behavioural consequences of altered brain development on behaviour in mice that have mutations in autism-associated genes. Our group have been investigating the functions of the CHD7 gene in brain development. CHD7 causes CHARGE syndrome when mutated, a complex human syndrome where children suffer from a range of birth defects in addition to autistic symptoms. We recently identified essential roles for CHD7 in the development and growth of the cerebellum. When CHD7 is mutated, we observe defects in specific areas of the cerebellum that have been linked to autism. The aim of this project will be to identify the exact causes of these defects and to uncover the specific processes that are defective when CHD7 is absent. This knowledge may help define specific therapies to target these processes in the future.In addition, we have used the powerful genetic methods available in the mouse to produce mutants in which CHD7 is removed specifically from the developing cerebellum. These new mouse mutants will enable us to determine to what extent these cerebellar defects cause autistic symptoms. Furthermore, we will take the same approach to determine the function of a related gene called CHD8, which was recently shown to be very strongly associated with autism in the human population, but without any of the birth defects typical of CHARGE syndrome. These studies will allow us to hone in on the specific causes of autism. This research will allow us to find answers to several important questions in autism research. We will identify the reasons why mutations in CHD7 and CHD8 can cause problems during brain development, the exact mechanisms whereby these factors control growth and development of the cerebellum and we will determine to what extent cerebellar defects are responsible for some of the core behavioural symptoms characteristic of autism. Taken together, our research will significantly improve our understanding of the causes of autism and define the importance of cerebellar defects in the development of autism. Our findings will create an important source of knowledge upon which future attempts to predict, diagnose, and possibly treat specific aspects of autism could be based.Technical SummaryAutism is a complex genetic disorder that affects social development. Recent advances have led to the identification of several autism-associated genes. This proposal will examine the neurodevelopmental role of two of these genes, the chromatin-remodelling factors CHD7 and CHD8. CHD7 is mutated in CHARGE syndrome, which is a syndromic form of autism. We have recently produced new mouse models that reveal key functions of CHD7 in the development of the cerebellum, a part of the brain that is consistently reported to show neuro-anatomical defects in autistic patients. We will use these mouse models to test important questions about the relationship between the genetic control of cerebellar development and autism. First, we will determine the developmental and epigenetic mechanisms that underlie these cerebellar defects. Second, we will use mouse models in which CHD7 is specifically deleted from the developing cerebellum to test to what extent cerebellar defects are responsible for some of the behavioural features characteristic of autism; a critical question remaining in the field. We will build on this model to explore the significant association of CHD8 haploinsufficiency with non-syndromic autism. CHD7 and CHD8 proteins directly interact and our preliminary studies suggest that CHD8 and CHD7 might regulate similar pathways during cerebellar development. To define the mechanisms whereby CHD8 deficiency causes autism, we will identify the functions of CHD8 in brain development and determine the behavioural consequences of CHD8 deletion from the developing cerebellum. Together, these studies will identify new epigenetic mechanisms that can cause cerebellar defects and determine the consequences of cerebellar hypoplasia, in the absence of primary defects in the neocortex, on behaviours characteristic of autism.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
