Neuronal vulnerability to ischaemia: the role of AMPA receptor trafficking.

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The aim of this research is to define mechanisms that contribute to the dysfunction or death of nerve cells in the brain following brain injury, such as a stroke, or other neurological disorders.Brain ischaemia occurs when the blood supply to a part of the brain is interrupted, for example by blockage of an artery (a stroke) or by heart failure. Brain damage caused by stroke has huge personal, social and economic impact. An estimated 150,000 people per year suffer from a stroke, making it the third most common cause of death in the UK. It is also one of the most common causes of severe disability, and more than 250,000 people live with disabilities caused by this condition. Nerve cells (neurons) in the brain need a constant blood supply to provide essential factors for life, especially oxygen and glucose, and without these factors, neurons malfunction and die. An intriguing aspect of ischaemia is that neurons in certain brain regions are more likely to die as a result of an ischaemic injury than others. The aim of this proposal is to investigate the mechanisms that underlie these differences, with the hope that the knowledge we gain from our research could be used to make vulnerable neurons less likely to die following brain ischaemia.Neurons communicate with each other via chemicals known as neurotransmitters, which are released from one neuron to be received by another via special receptors across a gap called a synapse. During the oxygen and glucose deprivation (OGD) associated with ischaemia, the properties of a very important type of neurotransmitter receptor (called the AMPA receptor), change in such a way that it allows more calcium than usual to enter neurons. It is this abnormal calcium entry that leads to neuronal death hours or days after brain ischaemia.We have shown that less vulnerable neurons respond to OGD with different alterations of AMPA receptor properties, which are likely to result in reduced calcium entry into the cell. We propose to study the molecular mechanisms that underlie how AMPA receptors change during OGD in the different types of neurons, and investigate the idea that subtle differences in the way AMPA receptors change at synapses has a profound influence on the likelihood that the neurons will die. Most of our experiments will be carried out using neurons obtained from the rat brain. These neurons can be isolated from the brain and then kept 'alive' in a petri dish. We will also use slices of rat brain that keep some of the important connections between neurons. Using these cells and slices we will be able to understand more about the mechanisms that occur in response to OGD in neurons. We will then modify these mechanisms using drugs or genetic techniques to see if we can stop neurons from dying.It has been shown that other disorders, including motor neuron disease and traumatic brain injury (physical impact injury), involve similar changes in AMPA receptors at synapses. This work will therefore provide crucial information about how neurons respond to a range of neurological disorders.