Manganese-iron interactions determining neuronal function and phenotype

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Manganese and iron are essential trace metals and critical for brain physiology anddevelopment. Dyshomeostasis of either metal leads to detrimental neurodevelopmental andneurodegenerative disorders.[1,2] Numerous transporters in the central nervous system areshared between manganese and iron, explaining why dyshomeostasis of one metal impactsthe other. SLC transporters including SLC30A10, SLC39A8 and SLC39A14 facilitate bothcellular manganese and iron uptake/export.[3] This project will explore the contribution ofmanganese-iron interactions to neuronal function, especially how perturbation of manganesemetabolism can modulate iron metabolism and together, alter neuronal function andphenotype.Objective 1: Determine the effect of manganese-iron interactions on neuronal function andbehaviour.Whole brain activity, anatomy and neurochemistry mapping at single-cell resolution as wellas in vivo calcium imaging will be performed in wild-type and SLC transporter mutantzebrafish to identify neuronal circuits dependent on strict metal homeostasis. There will be aspecial focus on the visual pathway as the zebrafish retina is particularly sensitive to metalperturbation.4 Visual and locomotor behavioural analysis will link functional/molecularchanges to altered behaviour. CRISPR/Cas9 will be used to determine the hierarchy ofmolecular events.Objective 2: Determine the effect of manganese-iron interactions on tissue and cellularcompartmental metal distributions and linking spatial changes to function under item 1.The student will attend the London Metallomics Facility to use laser ablation inductivelycoupled-plasma mass spectrometry (LA-ICP-MS) to generate quantitative "metal maps" (Mn,Fe, Zn, Cu) of the zebrafish brain and eye. Fluorescent iron probes will be used to assessrelative iron distributions between cellular compartments in zebrafish neuronal cultures,modulating function and behavioural phenotype.Dr Tuschl, expert in manganese neuroscience [1,3,4], will lead on the zebrafish imaging andbehavioural analysis in this project. Dr So, whose research focuses on the role of iron on brainageing and neurodegeneration, will provide expertise in iron homeostasis and quantitativemetal analysis/imaging.[2,5]