ZNF804A: connecting a confirmed schizophrenia risk gene to neuronal, network and behavioural function

Millions of motorists set out every morning and the majority of them manage to reach their destinations without incident. But with such a complex and busy network of roads, it does not take much for rush hour to go wrong: just one breakdown can mean gridlock, particularly if the system is already made vulnerable by roadworks. Brains are similar: normally they work well when left to their own devices, but complex diseases like schizophrenia (which afflicts around 1 in 100 people) emerge from very subtle causes, particularly in patients already made vulnerable, by drug abuse for example. Unfortunately, effective treatment of schizophrenia is still hampered by the fact that we do not know exactly what these complex causes are.
We do know that the most important vulnerability factor is family history. If you inherit a faulty secondhand car ? even if it works at first ? it may be you that breaks down and causes rush hour chaos. And if someone in your family has schizophrenia, genes you inherit from them increase your risk of developing the disease. Identifying these genetic faults is therefore critical, since it allows us to identify people at risk, to understand disease mechanism by studying the mechanics of what particular genes contribute to brain function, and hopefully to develop better treatments.
Our recent work surveying around 60,000 people, their genes and their diseases has identified variations in one particular gene consistently linked to schizophrenia. But for this information to be useful, we need to understand what the gene does and why particular versions of it put people at risk of developing debilitating psychotic, depressive and learning problems. To do this, we have engineered mice that also carry variations in the mouse equivalent of the schizophrenia-linked gene. This project will study brain structure, behaviour and brain activity of these mice to see if they share any features in common with schizophrenia patients (e.g. changes in anxiety, learning and memory, sleep). Although schizophrenia cannot be modeled fully in mice, showing that subtle variations of this gene cause symptoms reminiscent of the disease in animal models will provide direct evidence that it is the culprit. These models can then be used to develop and test better therapies that keep brain traffic flowing smoothly.

The recent confirmation of ZNF804A as a susceptibility gene for schizophrenia opens a rare entry point for studying the mechanistic basis of the pathogenesis of this disorder. However, at present, almost nothing is known about the in vivo functions of the encoded protein ZNF804A, or how it contributes to risk for psychopathology. To enable such studies, we have created a number of Zfp804a (the closely related murine orthologue) mutant mouse lines. Here we propose to exploit our development of these lines to allow, for the first time in the intact animal, a comprehensive and integrated characterisation of the functions of a common risk factor for schizophrenia at neurobiological and behavioural levels.
Our preliminary work has established that both ZNF804A and Zfp804a are discretely expressed in brain, particularly in striatal-limbic-cortical circuits associated with cognitive function and neuropsychiatric dysfunction. Consistent with this, our initial functional work has indicated altered behaviour in the Zfp804a mutants; hyperactivity and learning deficits. Capitalizing on expertise and resources in Cardiff and Bristol, we propose to examine relevant aspects of brain structure, behaviour and coordinated neuronal activity in the Zfp804a mutant mouse lines. Specifically, we will combine histological, immunohistochemical, behavioural and in vivo electrophysiological methods to establish whether dysfunction leads to altered brain structure, interneuronal properties, cognitive and emotion-related behaviours, sleep or coordinated limbic-cortical interactions.
Our rapid development and validation of the mutant lines provides a timely and powerful opportunity to define ZNF804A function across multiple scales by combining ongoing cellular work with the systems level analyses proposed herein. Main outcomes will include: (i) unique hypothesis-generating data on functional effects of Zfp804a mutagenesis; (ii) findings from animal work that will integrate with, and inform, ongoing work by the applicants using cellular models and clinical populations and (iii) creation of valid entry points for future work, examining how ZNF804A variants interact with genetic and environmental factors to, ultimately, modify psychiatric disease risk. The work will also establish an optimised experimental framework across the Cardiff and Bristol groups for use in examining other novel risk gene candidates as additional models become available.