Activation of AMPA-type glutamate neuroreceptors in health and disease

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The human brain contains about 86 billion neurons communicating with each other in a hugely complex network. Dynamic activity changes in this network form the basis of all our cognitive processes, such as memory formation and learning. Consequently, proteins that mediate neuronal communication form the molecular basis of theses cognitive processes and are essential pharmacological targets. This project focuses on one such protein: AMPA-type glutamate neuroreceptors. These glutamate-gated ion channels are found in the postsynaptic membrane of almost every excitatory synapse and their activity is crucial for propagation of the action potential. You will study a single-point mutant (Lurcher) which causes rare and complex neurodevelopmental disorders, including seizures, to understand the mechanism of disease and principles of activation of AMPA receptors at the single-molecule level, in a project encompassing both fundamental and applied science.Preliminary data shows this mutant slows activation of individual subunits within the tetrameric AMPA receptor, allowing us to investigate the mechanism of AMPA receptor activation as its subunits activate one by one. This part of the project addresses one of the main open questions in the field of glutamate-gated ion channels: do all four subunits contribute equally to the activation of an AMPA receptors? The applied aspect of the project focuses on studying the effects of perampanel, a commercially available drug used in treatments against epilepsy, on mutant AMPA receptors. This part of the project could help develop novel treatment options for patients carrying this mutation.The main experimental method will be patch-clamp electrophysiology, which enables us to record the activity of AMPA receptors at the macroscopic and single-molecule level. Single-molecule recordings are accompanied by extensive data analysis, therefore the candidate would develop both strong experimental and data analysis skills. The candidate will be working closely together on all aspects of the project (from experimental design, data collection and analysis to manuscript writing) with Dr. Baranovic (primary supervisor), who would also train them in patch-clamp electrophysiology. At the same time, the candidate would benefit from the extensive experience of Prof. Wyllie (second supervisor), in collaboration with whom they would have a chance to extend their patch-clamp experience to neuronal cultures. The project also entails interdisciplinary collaboration with Prof. Teuta Pilizota (University of Edinburgh), whose algorithm for step analysis of bacterial flagellar motor will be explored and adapted for analysis of stepwise activation of AMPA receptors.