The role of chromatin remodelling factors in cerebellar development and autism

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.

Autism 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.

A key component of our proposal is the assertion that specific cerebellar defects caused by mutations in chromatin remodelling factors are responsible for some of the behaviours characteristic of autism. As such, our research has the potential to benefit a range of clinical researchers and health professionals, students, patient and family groups. The knowledge of mechanisms that underlie autism to be gained in this study, may lead to the development of effective treatments and interventions that will have significant economic benefits by allowing people affected by autism to fully integrate in society and contribute to the economy.

Clinical research: In the short term, our research will have the most immediate impact on academic and clinical researchers interested in neurodevelopmental disorders. In particular, clinical researchers interested in the causes of autism and the role of the cerebellum in autistic behaviours, are likely to benefit from our studies, especially if we find strong evidence for cerebellar involvement in behaviours like social cognition, communication, repetitive behaviours and cognitive rigidity. Our findings are likely to stimulate further clinical research studies and trials to assess cerebellar defects in autistic patients and children deemed at risk of developing autism. A potential longer-term effect of our research that can be foreseen, is the development of improved methods for detecting alterations in cerebellar structure (e.g. by MRI) and connectivity (fMRI) that could be applied to screening and diagnosis.

Health professionals and patient groups: Eventually, in the longer term, our studies might be translated to the clinical setting where they will impact on approaches for the diagnosis and screening of patients. An improved understanding of the critical parts of the brain associated with particular autistic behaviours, and the underlying molecular mechanisms that can cause autism will be beneficial for patients, families and genetic counsellors.

Potential economic impacts: In the long-term, our findings might lead to the design and evaluation of specific treatments or therapies that target epigenetic processes to improve or alter relevant neuronal functions or processes. Although still a long way off, this study will begin to identify some of the epigenetic mechanisms that underlie phenotypes associated with autism, which could form the basis of further translational research.

Potential societal impacts:
Students and teaching: Applicants provide several lectures on epigenetics, neurodevelopment and disease and behaviour to undergraduate students at King's College London. The quality of these lectures is substantially improved by the use of topical examples from our research.

Basson contributes to outreach activities at King's College, in particular by lecturing on the Worshipful Company of Barbers' Science and Medicine in Action lecture series for 6th form students considering a career in the health sciences. The most popular lecture is one that examines the use of model organisms to dissect the mechanisms that control brain development and to study the causes of conditions like CHARGE syndrome and autism. Students are encouraged to think about the value of research and creation of knowledge in this lecture, a somewhat different approach than the other lectures that focus on clinical practice.

Wider public: Where appropriate, we strive to maximise the wide dissemination of our research to reach the wider public. This project, which aims to address several compelling and important questions about the causes of autism and behaviours inherently of great interest such as language and social interactions, has significant potential for public engagement. Wingate has a particularly strong history in public outreach in the art-science sector and will use his established networks to disseminate our research findings.