The effect of D-alanine and a prebiotic on rat brain N-methyl-D-aspartate (NMDA) receptors and executive function

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The NMDA glutamate receptor is important for brain functions such as memory and problem solving. A naturally occurring chemical called D-alanine can activate this receptor and may control the way we think, but its levels in the brain are quite low. We have often wondered whether increasing the amounts of D-alanine in the brain would activate the NMDA receptor more, and therefore make the thinking processes work better. Animals and people can drink a lot of D-alanine in water without making them feel ill. We have found that when rats drink D-alanine for a couple of weeks, it causes chemical changes to the NMDA receptor in the brain. Scientists have shown that the sorts of changes we see, make the NMDA receptor more active. We therefore want to prove that D-alanine increases NMDA receptor function, and if this also improves thinking. This information will be useful to people who are interested in stopping the decrease in brain function which happens as the brain gets older or when it is affected by an illness. We will feed rats with D-alanine for two and eight weeks and see if they are better at problem solving than animals not given the compound (controls). This will be done with the attentional set-shifting task which basically tests how many go's it takes the rats to work out where food is buried, by using the information they were taught before the actual test. After the tests we will use standard methods to measure chemical changes to NMDA receptors and the amounts of other brain molecules which sometimes change when the receptor is active. All this information should tell us if D-alanine helps the thinking process, and if it is related to certain chemical alterations in the brain. In separate experiments, rats will be fed with D-alanine as before, and while they are asleep we will measure their brain electrical activity produced by adding the chemical NMDA. We believe that the brains of D-alanine fed rats compared to controls will have more electrical activity after adding NMDA because, the NMDA receptor is more active in these animals. Scientists have known for a while that D-alanine in our bodies actually comes from the good bacteria in our guts. Some drinks and yoghurts, called prebiotics, make these bacteria grow more, and this makes us healthy because the bugs help breakdown the food we eat. When we fed rats with a prebiotic called fructo-oligosaccharide (FOS), we saw the same changes in the NMDA receptor in the brain as we previously saw with D-alanine feeding. We now want to see if FOS feeding does actually increase levels of D-alanine in the brain, and if it changes rat behaviour and brain electrical activity. Finally, we will add D-alanine to isolated brain cells (cell culture) and measure chemical changes to the NMDA receptor. If nothing happens, we will know that D-alanine can only change NMDA receptor chemistry when the brain is in the body. This means that other molecules, pathways and brain areas, which are not present in cell culture, are needed for D-alanine to affect the receptor. We will also test if D-alanine added to cells affect other chemicals without causing changes in NMDA receptor chemistry. Overall, the study will tell us if the thinking process and NMDA receptor activity can be increased after drinking D-alanine or a prebiotics. This is important to know because a lot of people take prebiotics with their food, and it is possible that these, or just D-alanine alone, can help brain function as we get older or develop a brain disease.