Characterising mice syntenic for human 16p11.2 duplications or deletions in relation to schizophrenia and autism

The impact of mental health on society is enormous. It is estimated that autism spectrum disorders (ASD) affect around 0.6% of the population and account for 0.3% of the global burden of disease, while schizophrenia affects ~1% of the population and is considered to be the 9th leading cause of disability worldwide. Effective pharmacological treatments for ASD do not exist, while current medications for schizophrenia have many unpleasant side-effects, are only active against the positive symptoms, and are ineffective in around 30% of patients; hence the majority of patients remain chronically impaired. New and improved treatments are urgently required.
We have some understanding of the neurobiological dysfunction associated with schizophrenia. In particular, the prefrontal cortex, an area involved in thought and planning, shows reduced metabolic activity in patients with the disease, along with the loss of cells that contain a relatively rare protein called parvalbumin and make the inhibitory brain chemical transmitter GABA. The picture is less clear with autism, possibly reflecting great variability in symptom severity. However, there are known to be deficits in the ability of different brain regions (parts of the cortex) to communicate with each other.
Genetic and environmental factors contribute to the risk of developing both autism and schizophrenia. The environmental risk factors implicated in these diseases seem to be distinct, but intriguingly, some genes are now thought to be linked to both diseases. In a few cases, there is a reciprocal relationship, where loss of a set of genes increases risk of one disease, while gain of the set of genes increases risk of the other. In the absence of any overtly opposite relationship between autism and schizophrenia, the study of such genes is potentially highly informative in terms of disease aetiology.
A segment of chromosome 16, encompassing 29 genes, is one such region: the loss of a copy increases the risk of autism dramatically, while gain of an extra copy of this same segment markedly increases risk of schizophrenia. Mice have been engineered to reproduce these genetic deletions and duplications.
In this project we will determine how these genetic changes in mice affect aspects of brain function that are analogous to parameters where patients show impairment. We will monitor cognitive performance, brain regional metabolic activity (including the prefrontal cortex), brain network connectivity , and also key proteins (including parvalbumin) expressed in affected brain regions. Using these mouse models, we will gain new insight into the causes of these diseases. In addition, these studies will validate the mouse strains as useful models for future drug development. Positive findings should have considerable impact for understanding these diseases and improving their treatment.

Autism spectrum disorders (ASD) and schizophrenia are both diseases which place a large health burden on society and upon individual patients and their carers. An understanding of the neurobiological effects of high penetrance (albeit rare) genetic variants has substantially advanced our understanding of many human diseases with complex genetic influences. Genetic factors exert powerful but complex effects on risk of both ASD and schizophrenia. Most of the risk reflects the action of common variants of small effect, but recent advances have revealed the influence also of rare variants of much larger effect. In a few cases, there is a reciprocal relationship on disease risk for small chromosomal deletions or duplications. The 16p11.2 locus provides a dramatic example. 16p11.2 deletions (DEL) dramatically increase risk for autism and intellectual disability, while in contrast duplications (DUP) of the same region markedly increase risk for schizophrenia. It is not clear how these opposing genetic changes impact on the development of these diseases, but the neurobiological effects of the genetic changes can be studied in mice with the equivalent genetic lesion.
In this programme of research, we propose to study mice with a deletion (DEL) or duplication (DUP) at the region of the genome corresponding to the 16p11.2 variants in humans. We will assess cognitive performance (using tests aligned to those where patients show deficits), CNS metabolic activity and functional connectivity (parameters that can be monitored in patients), and also glutamate receptor function and cortical neurochemistry (testing parameters known to be affected in patients). The neurochemical studies will illuminate the nature of the dysfunction caused by the lesion, and the behavioural and imaging studies will determine the extent to which the mouse strains can model aspects of the corresponding diseases, using highly translatable paradigms.

Apart from the clear academic beneficiaries of this proposal, it is anticipated that there will be direct beneficiaries in the pharmaceutical industry. This would apply to the UK commercial sector and also globally. The study of rare disease-causing genetic variants has advanced our understanding of a number of human diseases, including neurodegenerative and psychiatric diseases with a complex non-Mendelian genetic background. The research builds on recent evidence that patients with deletions or duplications at chr.16p11.2 have dramatically increased risk of autism or schizophrenia. Early evidence shows that mice with the corresponding genetic lesion reproduce some phenotypes associated with human 16p11.2 variants. Hence characterisation of the cognitive, neurological and neurochemical phenotypes of these mice is likely to illuminate the neurobiological basis of these diseases. There is a continuing and urgent need for better understanding of the neurobiological causes of autism and schizophrenia, and for improved translational pre-clinical models for aspects of these diseases. We consider it likely that the data produced in this programme of research would allow the mouse models of 16p11.2 CNVs to become important for pharmaceutical industry drug discovery programmes.
The award of the grant will significantly enhance the multidisciplinary research expertise at in the College of Psychology and Neuroscience at the University of Glasgow, the Centre for Neuroscience, University of Strathclyde, and the Division of Biomedical and Life Sciences, Lancaster University. This will provide leverage to increase the pool of PhD funded students in the Neuroscience and Mental Health arena as well as attract external research fellows who would benefit from being trained in the advanced technologies utilised in this project. Through PsyRING (research collaboration between Universities of Glasgow and Strathclyde, specialising in research partnerships focussed on psychiatric disease) we will continue to engage with our industrial collaborators and ultimately aim to develop joint programmes in drug discovery based upon the outcomes from this research programme.
The ultimate beneficiaries are patients with autism, schizophrenia and their families and carers. Improved drug treatments are urgently needed, and a new insight into the neurobiological basis of the disease may eventually lead to substantial improvements in their quality of life. These diseases are a major burden on the economy; for example the National Institute for Health and Clinical Excellence note that the societal cost of schizophrenia in England alone is £6.7 billion annually. Hence, while the ultimate ramifications of the research proposed are hard to predict, there is at the very least the potential for a significant economical and societal impact.