Fated to forget: An age-dependent decrease in Syd-1 causes age-dependent memory decline

Abstract

Most organisms experience an age-dependent decline in memory that is caused by a failure to maintain synapses, the connections between neurons. Despite the importance of maintaining synapses during adulthood, the molecular mechanisms responsible are unknown. In aging fruit flies, memory decline occurs because pre-synaptic sites called active zones (AZs) accumulate an excess of the essential structural component Bruchpilot (Brp), but why this happens is unclear. During development, Brp is recruited to AZs by the conserved AZ protein Syd-1. I tested the hypothesis that age-dependent changes in Syd-1 cause the age-dependent accumulation of Brp. I first used an enhancer trap to monitor Syd-1 expression during adulthood. I found that Syd-1 levels decrease with age, suggesting a model in which this decrease might be responsible for the age-dependent increase in Brp. To test this possibility, I asked whether prematurely reducing Syd-1 levels prematurely increases Brp. I found, indeed, that young flies who expressed less Syd-1 from the onset of adulthood onward had higher Brp levels than wild-type flies of the same age. From this, I can conclude that Syd-1 is required to prevent the accumulation of Brp. I next wanted to test whether preventing the age-dependent decrease in Syd-1 could delay or prevent the age-dependent increase in Brp. I found that overexpressing Syd-1 during adulthood is not sufficient to reduce Brp levels in younger or older adults, suggesting that additional genes contribute to this process. These results deepen our understanding of the components involved in aging that could be manipulated to delay this process.