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.Technical SummaryAutism 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.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
