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

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

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.

Technical Summary

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.

Publications

10 25 50
 
Description Member of the Lilly Centre for Cognitive Neuroscience
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Description Member of the P1vital Ltd Advisory Board
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Member of the Wellcome Trust Investigator Awards Funding Committee, Cellular and Molecular Neuroscience Expert Review Group
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Member of the funding committee for ANR (L'Agence Nationale de la Researche) France
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
 
Description Defining the disturbance in cortical glutamate and GABA function in psychosis, its origins and consequences, Experimental Medicine Challenge
Amount £4,252,721 (GBP)
Funding ID MR/K020803/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2014 
End 02/2018
 
Description Diverse serotonin 2C-receptor mediated behaviours resulting from snoRNA regulated post-transcriptional modification,
Amount £471,803 (GBP)
Funding ID BB/J016756/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2012 
End 09/2015
 
Description MRC Centenary Award, Identification of genome-wide targets for neurodevelopment
Amount £42,100 (GBP)
Funding ID G081418/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2012 
End 12/2012
 
Description MRC Centenary Award, Investigating enduring maternal effects on adult behaviour abnormalities in Zfp804a mutants
Amount £18,649 (GBP)
Funding ID G081418/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2013 
End 07/2013
 
Description MRC Centre Award
Amount £3,200,000 (GBP)
Funding ID MR/L010305/1 
Organisation Medical Research Council (MRC) 
Department MRC Centre for Neuropsychiatric Genetics and Genomics
Sector Academic/University
Country United Kingdom
Start 08/2014 
End 07/2019
 
Description WT Strategic Award DEFINE - Defining Endophenotypes from Integrated Neurosciences
Amount £5,234,843 (GBP)
Funding ID 100202/Z/12/Z 
Organisation Wellcome Trust 
Department Wellcome Trust Strategic Award
Sector Charity/Non Profit
Country United Kingdom
Start 08/2013 
End 07/2018
 
Description Wellcome Trust Seeding Drug Discovery Award Scheme
Amount £4,000,000 (GBP)
Funding ID G1345 
Organisation Wellcome Trust 
Department Wellcome Trust Translation Award
Sector Charity/Non Profit
Country United Kingdom
Start 08/2014 
End 07/2017
 
Title Zfp804a ENU point mutant mouse lines 
Description Creation of two Zfp804a (the mouse orthologue of the psychosis risk gene ZNF804A) ENU point mutation mouse lines from the ENU DNA library held at MRC Harwell. The Exon2 line is a nonsense mutation resulting in a premature stop codon. The Exon4 line is a missense mutation resulting in changes in amino acid sequence. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2011 
Provided To Others? Yes  
Impact research with these lines ongoing in Cardiff and Bristol 
 
Description MRC Neuromouse: An integrated and translational Research Consortium to study the dysfunction and degeneration of the nervous system. 
Organisation Medical Research Council (MRC)
Country United Kingdom 
Sector Public 
PI Contribution Collaboration on generating new genetic models. Disseminating best practice in behavioural analysis. Contributing to consortium meetings.
Collaborator Contribution Collaboration on generating new genetic models. Disseminating best practice in genetic and neurobiological analysis. Contributing to consortium meetings.
Impact Creation of novel mouse models ongoing. First Neuromouse consortium meeting in Jan 2012
Start Year 2012
 
Description Using psychiatric genetics and genomic approaches in drug discovery for psychiatric disorders 
Organisation Takeda Pharmaceutical Company
Country Japan 
Sector Private 
PI Contribution We are entering into a partnership with the pharmaceutical firm Takeda in order to generate targets and assays with higher predictive validity. We will contribute our knowledge in psychiatric genetics/genomics, our highly phenotyped clinical cohorts, and expertise in cellular and in-vivo models.
Collaborator Contribution We are in the final stages of agreeing £4M of funding from Takeda. In addition to the research funding Takeda will contribute particular expertise in target identification and validation.
Impact at the beginning of the partnership.
Start Year 2018
 
Description ZNF804A: connecting a confirmed schizophrenia risk gene to neuronal, network and behavioural function 
Organisation University of Bristol
Department School of Physiology, Pharmacology and Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Creation of Zfp804a ENU mutants modelling genetic risk factor for schizophrenia and bipolar disorder. Behavioural analysis of Zfp804a mutants.
Collaborator Contribution Structural, neurochemical and neurophysiological analysis of Zfp804a mutants
Impact Research programme ongoing
Start Year 2011
 
Description Talk to Swansea 41 Club Oystermouth Yacht Club, Swansea 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact About 30 members of the Swansea 41 Club attended to hear about our work on brain function and in particular the impact of psychiatric genetics on our understanding of brain disorders.

Lots of good feedback from the audience.
Year(s) Of Engagement Activity 2011
 
Description Talk to Swansea Ladies Tangent in top room of Italian Restaurant near football ground 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact About 30 members of the Swansea Ladies Tangent attended to hear about our work on brain function and in particular the impact of psychiatric genetics on our understanding of brain disorders.

Excellent feedback from the formidable ladies in the audience
Year(s) Of Engagement Activity 2012