PgmNr D1275: Scabrous mediates acute ethanol response in the Drosophila brain through the Notch pathway.

Authors:
M. Feyder; R. Muster; A. Ray; N. Mei; A. Mathur; E. Petruccelli; K. Kaun


Institutes
Brown University, Providence, RI.


Keyword: learning/memory

Abstract:

Alcohol use disorders (AUDs) take a significant social and medical toll on the world’s population. Drosophila have proven to be a useful genetically tractable model in which to investigate the molecular and behavioral effects of alcohol. We have previously shown that flies form long-lasting memories for the intoxicating properties of ethanol and identified the Notch pathway regulator scabrous (sca) as a potential molecular component of ethanol reward memory. Despite evidence that sca mutants exhibit several Notch-dependent developmental phenotypes, the general role of Notch signaling in the adult brain as well as in response to ethanol exposure remains poorly understood. Although Sca is known to bidirectionally regulate the Notch pathway in a context- and tissue-dependent manner, the exact mechanisms by which Notch and Sca interact in the adult fly brain is unclear. We predict that Sca mediates ethanol response in the mushroom body by promoting the cleavage of the Notch intracellular domain resulting in its activation. To test this, we used western blotting to characterize Sca effects on cleavage and processing of the Notch intracellular domain in adult fly heads. Compared to wild-type flies, sca mutants have increased levels of membrane-associated Notch and decreased levels of cleaved Notch, suggesting that Sca acts as a positive regulator of Notch pathway activity in this context. We also found that repeated exposure to intoxicating amounts of ethanol induces differential activation of the Notch pathway in wild-type and sca mutant flies, using both western blotting and a GFP reporter for Notch activation, suggesting that Sca affects the acute ethanol response of Drosophila by altering Notch cleavage and subsequent activation. Further work will investigate downstream targets of Notch, potentially illuminating its function in long-term memory formation and alcohol reward behavior.



Flybase Genetic Index:
1. FlyBase gene symbol: sca; FBgn: FBgn0003326
2. FlyBase gene symbol: N; FBgn: FBgn0004647