Regulation of dendritic and synaptic plasticity by metabolic reactive oxygen species

Supervisor:

Prof Matthias Landgraf

Plasticity is fundamental to neuronal development and function. Neurons adjust their excitability, connectivity and structure in response to changes in activity, yet how neurons sense their activity level and then instigate structural changes has remained unclear. We discovered that motorneurons monitor their activity by responding to reactive oxygen species (ROS), commonly thought of as destructive molecules that accumulate with age and degeneration. We find that ROS generated as metabolic byproduct of mitochondrial ATP synthesis as well as by NADPH oxidases are actually critical plasticity signals. Asking how neurons might sense ROS, 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.

The molecular mechanisms by which ROS signalling implements synaptic changes now need to be discovered. For example, how are different growth responses mediated in presynaptic axon terminals vs. postsynaptic dendrites? Do different ROS act in different synaptic compartments? What are the temporal dynamics of activity and ROS-induced synaptic plasticity, and is the process reversible? Are these activity & ROS-regulated structural adjustments necessary for learning and memory?

We have a strong track record of generating genetic tools for imaging. Working with a custom built confocal microscope this project will use live imaging of dendrites and axon terminals to determine the dynamics of activity and ROS induced structural plasticity. Electrophysiological recordings will provide a physiological correlate to structural adjustments. And genetics will lead to the discovery of additional signalling pathways and effectors downstream of activity induced ROS.

References:

1. 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.
2. 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
3. Milton, V. J. et al. Oxidative stress induces overgrowth of the Drosophila neuromuscular junction. Proc Natl Acad Sci U S A 108, 17521–17526 (2011).
4. Couton L., Mauss A.S., Yunusov T., Diegelmann S., Evers JF., Landgraf M. Development of connectivity in a motoneuronal network in Drosophila larvae. Curr Biol. 25:568-76 (2015).  doi: 10.1016/j.cub.2014.12.056.
5. Oswald, M. C. W., Garnham, N., Sweeney, S. T., & Landgraf, M. (2018). Regulation of neuronal development and function by ROS. FEBS Letters. http://doi.org/10.1002/1873-3468.12972