Regulation of neuronal plasticity by NADPH oxidases

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The ability to remain plastic is a fundamental property of nerve cells. It is critical for learning and adaptation, as well as for protective responses to over-excitation caused by injury or disease. We study basic questions, such as: "How do nerve cells measure how active they are?" or: "What mechanisms transform changes in nerve cell activation into changes of nerve cell structure and connectivity?" We work with the fruit fly, Drosophila. The high evolutionary conservation of basic cellular processes has meant that most discoveries made in this model system are directly pertinent to our understanding of the human brain, including mechanisms that underlie learning and memory. Importantly, the fruit fly is one of the most powerful genetic experimental organisms. For example the larva of the fruit fly is one of the few model systems whose brain circuitry has been charted close to completion and where one can genetically manipulate individual connecting neurons with unrivalled precision. We recently discovered that nerve cells use reactive oxygen species (ROS) as signals to monitor their own activity levels. ROS levels are well known to increase in the brain with ageing and to reach pathological levels in many neurodegenerative conditions, including Alzheimer's, Parkinsonism or Motorneuron Disease. Nerve cells closely regulate the size of their synaptic terminals and the number of connections to other nerve cells. We found that at normal physiological levels ROS regulate this process. Some ROS are produced by mitochondria as constitutive by-products of their energy/ATP metabolism. This finding suggests that nerve cells might use metabolic ROS signals as a readout of their activity levels. As a cellular sensor for ROS we identified the conserved redox sensitive protein DJ-1b (Park7), which regulates synaptic terminal size through the PI3Kinase growth pathway.More recently we discovered that ROS produced in different sub-cellular compartments of nerve cells regulate different aspects of synaptic terminal plasticity. In this proposal we focus on ROS generated at the plasma membrane by NADPH oxidases. These regulate the size of synaptic terminals, as contrasting with mitochondrially produced ROS, which control how densely such terminals are populated with synapses. NADPH oxidases are best known for their roles in the immune system. In the nervous system they are thought to be required for learning associated plasticity, and a recent study suggests that their dysregulation could cause psychiatric conditions, such as schizophrenia. The first aim of our proposal is to determine how structural changes of synaptic terminals are paralleled by physiological functional alterations. Using state of the art imaging methods we will determine the role of NADPH oxidases in regulating activity-dependent connectivity in the central nervous system (CNS). Next, to determine how neuronal activity regulates NADPH oxidase activation, we will seek to identify interacting regulatory proteins and probe interactions with other signalling pathways known to regulate synaptic terminal growth. Our third aim explores the potential of NADPH oxidases to orchestrate the complex inter-cellular interactions that take place during neuronal remodelling: between neurons, their extracellular environment and adjacent glial cells. By producing ROS signals within the inter-cellular space, NADPH oxidases are ideally placed for coordinating local intercellular interactions, potentially signalling pathways conserved between the immune and nervous system.In summary, we aim to understand fundamental mechanisms of plasticity, which might be compromised in the ageing brain. Though our work is basic science it has the potential to aid the discovery of drugs and treatments that could alleviate adverse effects of ageing and might thus, in time, benefit society.