Control of neuroprotection through NMDA receptor-dependent regulation of antioxidant status.

Nerve cells (neurons) communicate by releasing chemical messengers onto each other, which are detected by specialised receptors. Low-level activation of an important receptor, the NMDA receptor (NMDAR), causes activation of signals that improve a neuron‘s chance of survival. We aim to understand the exact nature of these signals. Understanding the brain‘s natural neuroprotective mechanisms is important, since malfunction of these mechanisms may contribute to neurodegeneration in certain debilitating disorders (e.g.Alzheimer‘s, ALS, Parkinson‘s), and also neurodevelopmental disorders associated with too little NMDAR activity (e.g.Foetal Alcohol Syndrome). In contrast to the beneficial effects of modest NMDAR activity, too much NMDAR activation can kill neurons. This can occur when the brain is starved of blood supply, as happens in a stroke, and can even happen in certain neurodegenerative diseases. However, these disorders cannot be treated by blocking the NMDAR with drugs, since this is harmful too. We will investigate how blocking downstream consequences of NMDAR overactivation, rather than the NMDAR itself, can protect neurons in models of disease and injury, possibly leading to therapeutic targets for stroke or novel treatments. Our investigations will include studies on stem cell-derived human neurons, a theoretically limitless source of neurons with potentially increased relevance to human disease.