Reactive Oxygen Species Regulate Activity-Dependent Neuronal Structural Plasticity

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• Matthew Oswald (Landgraf lab, Department of Zoology)
• Wednesday 21 September 2016, 17:30-19:30
• Gurdon Institute Tea Room.

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Neurons are inherently plastic and adjust their electrical properties but also the size of their synaptic arbors in response to changes in activity. Such adjustments are usually homeostatic and allow cells to maintain a pre-determined activity range, promoting network stability and physiologically appropriate function. While homeostatic changes to electrical and transmitter release properties have been studied extensively, the mechanisms that regulate structural adjustment of synaptic terminal arbors have remained largely unexplored. We asked: How do neurons sense changes in activity, and by what mechanisms are these converted into structural changes at synaptic terminals? Working with identified motoneurons we studied structural adjustment in response to elevated activity in both their postsynaptic dendritic arbors in the CNS and their presynaptic neuromuscular junctions (NMJs) in the periphery. We discovered that motoneurons use metabolic by-products, namely Reactive Oxygen Species (ROS), a constitutive by-product of mitochondrial ATP synthesis, as readout for neuronal activity. We find that ROS , and hydrogen peroxide (H2O2) in particular, are necessary for activity-dependent synaptic terminal growth and sufficient for instigating such growth in the absence of elevated neuronal activity. We next identified a putative redox sensor, the Parkinson’s disease-linked protein DJ-1b. DJ-1b, in response to elevated H2O2 (but not O2-), inhibits the lipid-phosphatase PTEN and in doing so permits increased signalling via PI3K . PTEN and PI3K have been extensively linked with neuronal growth and energy metabolism and are therefore perfectly placed to expedite homeostatic growth in response to elevated neuronal activity and ROS . Until recently, ROS were primarily considered to be a tolerated burden, rapidly removed by a range of cellular ROS -buffering and scavenger systems. Accumulation of ROS , termed Oxidative Stress, results in changes in chromatin configuration and gene expression, lipid oxidation and cell death, leading to neurodegenerative pathology. Our work suggests a role for ROS during normal development and

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