We have been studying the causes of age-related memory impairment (AMI) in Drosophila, and have found that aging causes an increase in amounts of a glial protein, pyruvate carboxylase (PC). Reducing PC amounts delays AMI, while increasing PC amounts accelerates AMI. We have further found that PC inhibits synthesis of D-serine, a gliotransmitter required for normal neuronal function. This suggests that AMI may be caused by a reduction in D-serine. Supporting this model, we have shown that feeding old flies D-serine ameliorates AMI. Our results led us to propose a model where neuronal activity stimulates an inhibitory feedback pathway consisting of increases in PC and decreases in D-serine. This pathway normally prevents overexcitation of neurons, but aging leads to hyperactivity of this pathway and AMI.
We have also been studying neuronal apoptosis as a secondary cause of AMI. We propose that formation of long-term memories (LTM), which is important for organisms, is also inherently stressful to them. Neurons in young flies are able to withstand this stress, while neurons in old flies die. To test this hypothesis, we developed a biochemical assay to accurately quantify apoptosis in fly heads, and we are in the process of comparing apoptosis in young and old flies that are either naive or have been trained to form LTM.
In our studies of the relationship between sleep and memory formation, we have identified a compound that increases sleep and improves memory formation. We have also identified other compounds that decrease sleep and decrease memory.