Schizophrenia is a severe psychiatric illness that cause psychosis, depression and cognitive impairment. Genetic variation plays a key role in determining susceptibility to schizophrenia, but we do not understand how genetic differences lead to symptom-related abnormalities in brain function. This lack of understanding limits development of new therapies. SETD1A is one of few genes identified in both GWAS and exome sequencing of patients as underlying a substantially increased risk of schizophrenia. SETD1A encodes a histone methyltransferase that epigenetically regulates many downstream targets, including genes involved in neuronal maturation and synaptic signalling. Adult SETD1A knockout mice have behavioural endophenotypes disease-relevant (Isles), but schizophrenia is rooted in abnormal brain development. Therefore, we will assess the impact of SETD1A on the developmental process itself by measuring cellular, circuit and behavioural phenotypes as they emerge early in life.
As such, the key research question is how and when neural circuitry and associated activity goes awry during postnatal development of SETD1A deficient mice. To address this question, the student will have 3 specific objectives: -Pinpoint how and when maturation of neocortical activity diverges from normality in SETD1A knockout mice (Ashby). -Establish behavioural developmental milestones to determine when social deficits emerge in SETD1A knockout mice (Cahill/Ashby/Isles/Mary Lyon Centre -MLC). -Define the epigenetic and transcriptomic links between SETD1A knockout mice and schizophrenia patients (Mill) Experimental details:
In the Ashby lab, the student will learn in vivo imaging of head-fixed, behaving neonatal mice that express a fluorescent reporter of neuronal activity to assess development of cortical neural dynamics. These experiments benefit from bespoke adjacent rodent housing and surgical/experimental labs. To assess synaptic development, the student will learn whole cell patch clamp electrophysiology in acutely-prepared brain slices. Between Bristol and the Mary Lyon Centre, we will measure behavioural developmental milestones via customised homecage video monitoring and ultrasonic vocalisation recording to determine when social deficits emerge (Cahill/Ashby/Isles/MLC). This element benefits directly from the newly-funded National Mouse Genetics Network that links Ashby/Isles to the Mary Lyon Centre in a project designed to establish home-cage monitoring across the early life period in mouse models of schizophrenia. The students will therefore benefit from their project being embedded in this UK-wide network, facilitating training and development at Bristol and in visits to the MLC. In the Mill lab, the student will use bioinformatics to analyse epigenetic data from human brain tissue to compare disease-associated differences with those in the SETD1A mouse. Furthermore, the student will investigate the epigenetic and transcriptomic regulation of selected target genes in SETD1A mouse tissue, linking to aberrant neurophysiological findings. All these approaches and training needed are in place across the supervisors’ labs.
During the setup period, the student will have the chance to visit each host lab and the MLC to understand the experiments. While focus will remain on understanding of SETD1A in brain development, the balance of future directions can be shaped by the preferences and skills of the student. The student will receive training in each experimental approach, but can then emphasise particular directions. For example, should the student take to brain slice electrophysiology, then we can pursue a more synaptic development angle, whereas the cortex-wide in vivo imaging would allow us to develop a more circuit-based analysis, dependent on the student preference. They will therefore also have the chance to shape how much time they spend at each Institution.
ABOUT THE GW4 BIOMED2 DOCTORAL TRAINING PARTNERSHIP
The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP has already awarded over 90 studentships across 6 cohorts in its first phase, along with 38 students over 2 cohorts in its second phase.
HOW TO APPLY
Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’ on GW4 BioMed MRC DTP - GW4 BioMed MRC DTP
Please complete the online application form linked from the DTP’s website by 5.00pm on Wednesday, 1st November 2023. If you are shortlisted for interview, you will be notified from Tuesday 19th December 2023. Interviews will be held virtually on 24th and 25th January 2024. Studentships will start on 1st October 2024.
If successful, you will also need to make an application for an 'offer to study' at University of Bristol - Physiology, Pharmacology and Neuroscience | Study at Bristol | University of Bristol
For enquiries relating to the DTP programme or funding, please contact [Email Address Removed]
Please contact the project supervisor for project-related queries.