Regulation of neuronal 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. Understanding the underlying mechanisms will be important for future therapeutic approaches that seek to modulate the ROS burden associated with ageing and neurodegenerative conditions.

The aim of this project is to investigate: - the roles of ROS generating enzymes (NAPDH oxidases) and aquaporin channels during activity-regulated signalling, within nerve cells and between them; - the downstream plasticity pathways through which these act. 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 to characterise the consequences of critical period manipulations, with synaptic resolution, complemented by behavioural assays

Importance of the are 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, Coulson B, Miller M, Oswald MCW, Pettini T, Bailey DMD, Baines RA, Landgraf M. Mitochondrial ROS and HIF-1α signaling mediate synaptic plasticity in the critical period. PLoS Biol. 2025 Aug 13;23(8):e3003338.

doi: 10.1371/journal.pbio.3003338. Epub ahead of print. PMID: 40802851.Krick N, Davies J, Coulson B, Sobrido-Cameán D, Miller M, Oswald MCW, Zarin AA, Baines RA, Landgraf M. (2025).

Heterogeneous responses to embryonic critical period perturbations within the Drosophila larval locomotor circuit. bioRxiv 2024.09.14.613036; doi: https://doi.org/10.1101/2024.09.14.613036 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