The goal of this proposal is to identify genes that regulate an age-dependent change in active zones (AZs) that causes an age-dependent decline in neuron function. Nearly all organisms, including humans, decline in function as they age. Nervous systems are particularly vulnerable, as most neurons appear not to be replaced when damaged. Recent work in Drosophila has identified a molecular change in aging AZs that causes age-dependent decreases in memory. The conserved AZ component Bruchpilot (Brp), the fly ortholog of vertebrate ELKS/CAST proteins, increases throughout the brain during adulthood, resulting in significantly enlarged AZs in older animals. Increasing the lifetime dose of endogenous Brp results in large AZs and memory deficits in young adults, similar to those in wild-type old adults, indicating that the age-dependent accumulation of excess Brp at AZs is sufficient to cause nervous system deficits. Recent evidence indicates that MB neurons provide a signal that regulates Brp accumulation in other neurons. The nature of this signal and the cell-autonomous mechanisms by which neurons regulate their accumulation of Brp in response to this signal remain unclear. Doubling or halving the lifetime dosage of endogenous brp correspondingly accelerates or delays the age-dependent accumulation of Brp. This suggests that altering the lifetime dosage of regulators of this process may also either accelerate or delay Brp accumulation. To identify regulators, this application therefore proposes to:
(Aim 1) alter the dosage of conserved genes known to regulate Brp assembly during development and plasticity and identify those that have effects on age-dependent Brp accumulation;
and (Aim 2) systematically screen a collection of molecularly-defined deletions that span the Drosophila genome for those that alter age-dependent Brp accumulation and identify the causative genes. This work is can be completed in a limited amount of time but is potentially of high impact and an ideal project in which to engage undergraduate students. The genes identified will form the basis for future work on understanding the signals and cell-intrinsic mechanisms that cause AZs to change with age.
Most aging animals, including humans, experience a decline in nervous system function that is caused in part by changes to the properties of the synaptic connections between neurons. Recent work in Drosophila has identified a conserved synaptic protein, Bruchpilot/ELKS, that increases in amount with age, causing defects in memory. The purpose of this proposal is to identify genes that affect the age- dependent increase in Brp, with the ultimate goal of understanding how to prevent it.
