Image: Neuromuscular junction in the Drosophila larva. Motorneuron terminal size (brown), number of synaptic release sites (blue) and of mitochondria (yellow) are all regulated by ROS signals. Inset shows STED super-resolution image of postsynaptic receptor fields (magenta) juxtaposed to presynaptic release sites (green).
Regulation of dendritic and synaptic plasticity by metabolic reactive oxygen species
Supervisor: Professor Matthias Landgraf
Plasticity is fundamental to neuronal development and function. Neurons adjust their excitability, connectivity and structure in response to changes in activity. We discovered that motoneurons monitor their activity by responding to reactive oxygen species (ROS). ROS have commonly been thought of as destructive molecules that accumulate with age and degeneration. We identified ROS as important plasticity signals in the nervous system, suggesting energy homeostasis as central to activity-regulated changes; and ROS generating NAPDH oxidase enzymes and aquaporin channels for intercellular signalling.
The molecular mechanisms by which ROS signalling implements neuronal adjustment now need to be discovered. We identified the highly conserved, Parkinson’s disease-linked protein DJ-1b as a redox sensor, and PTEN/PI3Kinase as an effector pathway regulating synaptic terminal size. We are now working to identify the plasticity pathways that are regulated by these distinct sources of ROS.
Type of work
This project allows for a range of techniques to be used, from large data ‘omics approaches to opto-and thermo-genetics for targeted manipulations; super-resolution imaging (e.g. ExM and STED) and electrophysiology (2-electrode voltage clamp) to characterise the consequences of critical period manipulations, with synaptic resolution, complemented by behavioural assays.
Importance of the area of research concerned
We discovered ROS as adaptive signals during nervous system development, contrary to the commonly held view of ROS as toxic radicals. How ROS signal to bring about change now needs to be understood, to create the foundations on which future therapeutic approaches can build.
References
Sobrido-Cameán D, Oswald MCW, Bailey DMD, Mukherjee A, Landgraf M. (2023). Activity-regulated growth of motoneurons at the neuromuscular junction is mediated by NADPH oxidases. Front Cell Neurosci. 16:1106593. doi: 10.3389/fncel.2022.1106593.
Dhawan S, Myers P, Bailey DMD, Ostrovsky AD, Evers JF, Landgraf M. Reactive Oxygen Species Mediate Activity-Regulated Dendritic Plasticity Through NADPH Oxidase and Aquaporin Regulation. Front Cell Neurosci. 2021 Jul 5;15:641802. doi: 10.3389/fncel.2021.641802. PMID: 34290589; PMCID: PMC8288108.
Oswald MCW, Brooks PS, Zwart MF, Mukherjee A, West RJH, Giachello, CNG, Morarach K, Baines RA, Sweeney ST and Landgraf M. (2018). Reactive Oxygen Species Regulate Activity-Dependent Neuronal Structural Plasticity. eLife, 7. http://doi.org/10.7554/eLife.39393
Coulson B, Hunter I, Doran S, Parkin J, Landgraf M, Baines RA. (2022). Critical periods in Drosophila neural network development: Importance to network tuning and therapeutic potential. Front Physiol. 2022 Dec 2;13:1073307. doi: 10.3389/fphys.2022.1073307.