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Defining the mechanism of action of protein aggregates on hippocampal microcircuit function

Principal Supervisor: Dr Mark Wall 

Secondary Supervisor(s): Dr Emily Hill and Professor Magnus Richardson

University of Registration: University of Warwick

BBSRC Research Themes:

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Deadline: 4 January, 2024


Project Outline

This project will bridge the fields of experimental neuroscience and theoretical computational mathematical modelling. Whole cell patch clamp and extracellular recording will be used to explore the way in which hippocampal neurons and the hippocampal microcircuit responds to protein aggregates. Acquisition of such network information will be greatly assisted by the production of simplified computational models, which allow the simulation of large networks without requiring large amount of computational power. In order to translate the initial electrophysiology data into a network model, MATLAB (and Julia) will be used to generate dynamic IV curves. These can then be compared across different cell types and conditions.

The aggregation and accumulation of toxic protein species (such as tau, amyloid and a-synuclein) is commonly found in ageing and probably contributes to cognitive decline. One of our major aims is to determine what neuronal cell types are affected by these aggregates and how this leads to changes in emergent circuit outputs (such as oscillations) during the ageing process. For example, we have recently discovered that tau aggregates enhance the magnitude of a transient inward current in hippocampal neurons leading to increased burst firing. Tau aggregates also modulate the properties of synaptic transmission at the mossy fibre to CA3 pyramidal neuron synapse. The experimental side of this project will focus on understanding the mechanisms underlying these effects of tau and the effect on circuit function.

By combining both experimental neuroscience and theoretical computational mathematical modelling, the project will offer training in a wide range of different techniques and will offer a fantastic opportunity for development.

References

Badel L, Lefort S, Berger TK, Petersen CC, Gerstner W, Richardson MJ. Extracting non-linear integrate-and-fire models from experimental data using dynamic I-V curves. Biol Cybern. 2008 Nov;99(4-5):361-70. doi: 10.1007/s00422-008-0259-4. Epub 2008 Nov 15. PMID: 19011924; PMCID: PMC2798053.

Hill E, Wall MJ, Moffat KG, Karikari TK. Understanding the Pathophysiological Actions of Tau Oligomers: A Critical Review of Current Electrophysiological Approaches. Front Mol Neurosci. 2020 Aug 20;13:155. doi: 10.3389/fnmol.2020.00155. PMID: 32973448; PMCID: PMC7468384.

Brown J, Camporesi E, Lantero-Rodriguez J, Olsson M, Wang A, Medem B, Zetterberg H, Blennow K, Karikari TK, Wall M, Hill E. Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations. Acta Neuropathol Commun. 2023 Apr 24;11(1):67. doi: 10.1186/s40478-023-01562-5. PMID: 37095572; PMCID: PMC10127378.

Techniques

  • Whole cell patch clamp electrophysiology
  • Extracellular recording
  • Immunohistochemistry
  • Cell Culture
  • Molecular Biology
  • Computational Modelling