Manganese-iron interactions determining neuronal function and phenotype

Manganese and iron are essential trace metals and critical for brain physiology and
development. Dyshomeostasis of either metal leads to detrimental neurodevelopmental and
neurodegenerative disorders.[1,2] Numerous transporters in the central nervous system are
shared between manganese and iron, explaining why dyshomeostasis of one metal impacts
the other. SLC transporters including SLC30A10, SLC39A8 and SLC39A14 facilitate both
cellular manganese and iron uptake/export.[3] This project will explore the contribution of
manganese-iron interactions to neuronal function, especially how perturbation of manganese
metabolism can modulate iron metabolism and together, alter neuronal function and
phenotype.
Objective 1: Determine the effect of manganese-iron interactions on neuronal function and
behaviour.
Whole brain activity, anatomy and neurochemistry mapping at single-cell resolution as well
as in vivo calcium imaging will be performed in wild-type and SLC transporter mutant
zebrafish to identify neuronal circuits dependent on strict metal homeostasis. There will be a
special focus on the visual pathway as the zebrafish retina is particularly sensitive to metal
perturbation.4 Visual and locomotor behavioural analysis will link functional/molecular
changes to altered behaviour. CRISPR/Cas9 will be used to determine the hierarchy of
molecular events.
Objective 2: Determine the effect of manganese-iron interactions on tissue and cellular
compartmental 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 assess
relative 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 and
behavioural analysis in this project. Dr So, whose research focuses on the role of iron on brain
ageing and neurodegeneration, will provide expertise in iron homeostasis and quantitative
metal analysis/imaging.[2,5]