Computational Modelling of Dysfunctional Synaptic Plasticity in Neuropsychiatric Disorders

The project
This project will develop data-driven computational models of calcium signalling at synapses to understand how genetic mutations may lead to altered synaptic plasticity and learning in neuropsychiatric disorders. It will involve computational modelling, statistical model fitting to physiology data, and mathematical analysis of the model’s nonlinear dynamics.

This project will focus the effects of mutations in one particular gene: Cacna1c, which encodes the alpha subunit of Cav1.2 (L-type) voltage- gated calcium channels. These ion channels are expressed at synapses and are key mediators for synaptic plasticity induction and neuronal gene expression. Mutations in CACNA1C have been linked with a range of neuropsychiatric disorders such as schizophrenia, bipolar disorder, and ASD. However, we believe the insights will be generally applicable to other disorders.

The project will have three phases: 1. Build a computational model of postsynaptic calcium signalling dynamics at rodent hippocampal synapses, with particular emphasis on the L-type calcium channel. This model will be built using Python or Julia programming language and adapted from a model recently developed in the lab of lead supervisor O’Donnell at Bristol. 2. Use statistical optimisation tools to fit the model’s parameters to electrophysiology data from wild type mice and Cacna1c -/- mice recorded in the lab of co-supervisor Hall at Cardiff. Use the model to test whether differences in L-type calcium channel properties can explain effects on synaptic plasticity. 3. Use model reduction techniques to derive a compact form of the synapse model and analyse the reduced model with mathematical tools from nonlinear dynamics, in the group of co-supervisor Tsaneva-Atanasova at Exeter.

URL for further information:
https://www.gw4biomed.ac.uk/wp-content/uploads/sites/9/2020/09/MRC21NMHBr-ODonnell.pdf

How to apply
In the first instance online at MRC GW4 BioMed: https://www.gw4biomed.ac.uk/doctoral-students/

Candidate requirements
Applicants must hold/achieve a minimum of a Masters degree (or international equivalent) in a relevant discipline. Applicants without a Masters qualification may be considered on an exceptional basis, provided they hold a first-class undergraduate degree. Please note, acceptance will also depend on evidence of readiness to pursue a research degree.

Basic skills and knowledge required
• Essential: Programming experience in a modern scientific language e.g. Python/MATLAB/Julia. Demonstrable interest in neuroscience.
• Desirable: Training in one or more of the following disciplines: neuroscience; computer science; applied mathematics; physics; engineering.

Funding
GW4 BioMed MRC DTP studentships are available to UK, EU and International applicants. International and EU students are eligible to apply for these studentships but should note that they may have to pay the difference between the home UKRI fee and the institutional International student fee.

Candidates can check the eligibility criteria for the award at https://www.gw4biomed.ac.uk/doctoral-students/ .

Stipends will be paid at the basic UKRI rate: £15,285 per annum tax free for 2021/2022, typically rising each with inflation thereafter.

Contacts
For questions about the research topic please contact Dr Cian O’Donnell at [Email Address Removed]
https://odonnellgroup.github.io

For questions about eligibility and the application process please contact SCEEM Postgraduate Research Admissions [Email Address Removed]