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Regulation of dendritic and synaptic growth by metabolic reactive oxygen species

Regulation of dendritic and synaptic growth by metabolic reactive oxygen species

Supervisor: Dr Matthias Landgraf

Project summary:

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 the levels of reactive oxygen species (ROS), a metabolic byproduct of mitochondrial ATP synthesis. We identified the highly conserved, Parkinson’s disease-linked protein DJ-1b as a redox sensor, which regulates pre- and post-synaptic structural plasticity via the PI3Kinase pathway.

This discovery of ROS as a key second messengers in structural adaptive plasticity in the nervous system requires us to review the common perception of ROS as destructive molecules.

We now seek to address several important questions, including: what are the downstream mechanisms that implement different growth responses 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?

 

What the student will be doing:

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.     Oswald MCW, Brooks PS, Zwart MF, Mukherjee A, West RJH, Morarach K, Sweeney ST and Landgraf M. (2016). Reactive Oxygen Species Regulate Activity-Dependent Neuronal Structural Plasticity.  bioRxiv 081968.  

 2.     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).

 3.     Zwart, M. F., Randlett, O., Evers, J. F. & Landgraf, M. Dendritic growth gated by a steroid hormone receptor underlies increases in activity in the developing Drosophila locomotor system. Proc Natl Acad Sci U S A (2013). doi:10.1073/pnas.1311711110

 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.         Tripodi, M., Evers, J. F., Mauss, A., Bate, M. & Landgraf, M. Structural homeostasis: compensatory adjustments of dendritic arbor geometry in response to variations of synaptic input. PLoS Biol 6, e260 (2008).