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

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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.