The effect of free radicals on synaptic function and connectivity within individual neuronal connections and neuronal circuits

Overview

Oxygen is the single most important source of energy we need to keep us alive and functional. The ‘greediest’ user of oxygen in our bodies is our nervous system – our brain, spinal cord and all the nerves that provide the signals needed for us to think and move. The body has many ways to ensure the right amount (and chemical type) of oxygen is available where it is needed. This is vital because too much, too little or the wrong type of oxygen can be very detrimental to nervous system function. For example, a long-term failure to control oxygen level and chemical type has been linked to decline in motor (movement) and cognitive (thinking) function seen in many diseases associated with old age.

This project aims to understand how such a failure can alter the way nerve and muscle cells communicate with each other. It will measure the changes seen, uncover the mechanisms by which detrimental changes occur and link these changes to problems with motor and cognitive function all too commonly seen in the ageing population.

In detail

Oxygen is the single most important source of energy we need to keep us alive and functional. The ‘greediest’ user of oxygen in our bodies is our nervous system – our brain, spinal cord and all the nerves that provide the signals needed for us to think and move. The body has many ways to ensure the right amount (and chemical type) of oxygen is available where it is needed. This is vital because too much, too little or the wrong type of oxygen can be very detrimental to nervous system function. For example, a long-term failure to control oxygen level and chemical type has been linked to decline in motor (movement) and cognitive (thinking) function seen in many diseases associated with old age.

This project aims to understand how such a failure can alter the way nerve and muscle cells communicate with each other. It will measure the changes seen, uncover the mechanisms by which detrimental changes occur and link these changes to problems with motor and cognitive function all too commonly seen in the ageing population.

We have set up two forms of physiological recording for Drosophila larvae. We are examining the output of the motor system in Drosophila larvae to measure 'fictive crawling'; an output of the central pattern generator. We will use this measurement to assess the effect of oxidative stress on patterned behaviour and physiological output. In parallel we will examine the output of single neuromuscular synapses. We have determined previously that neuromuscular synapse growth is enhanced in response to oxidative stress and we will determine the physiological consequence of this growth. We are also utilising the ability to generate streams of pure oxygen radicals using the cold plasma source. We are subjecting Drosophila larvae to excess free radicals and using genetic reporters and organismal survival to assess exposure to oxidative stress. We are also testing the survival of larvae deficient for protection from oxidative stress to exposure to free radicals from this source. We are in the early stages of this study and look forward to reporting our findings.

Outputs

Grants

• Sean Sweeney, Alzheimer's Society, Dissecting the cellular mechanisms driving disease progression in CHMP2B activated Frontotemporal Dementia, £229,413
• Sean Sweeney, MRC, Interaction of Rab8 with OCRL1: Synaptic growth function in Frontotemporal Dementia and the Neurodevelopmental disorder Lowe Syndrome, £426,419
• Sean Sweeney, BBSRC, Reactive Oxygen Species, metabolic by-products of mitochondrial respiration, as conserved regulators of synapse growth and neuronal homeostasis, £208,343