Glial control of sphingolipid levels sculpts diurnal remodeling of circadian circuits

Abstract

Structural plasticity in the brain often necessitates dramatic remodeling of neuronal processes and attendant reorganization of the cytoskeleton and membranes. While cytoskeletal restructuring has been studied extensively, how lipids might orchestrate structural plasticity remains unclear. We show that specific glial cells in Drosophila produce Glucocerebrosidase (GBA) to locally catabolize sphingolipids. Sphingolipid accumulation drives lysosomal dysfunction, causing gba1b mutants to harbor protein aggregates that cycle across circadian time and are regulated by neural activity, the circadian clock, and sleep. While the vast majority of membrane lipids are stable across the day, a specific subset, highly enriched in sphingolipids, cycles daily in a gba1b-dependant fashion. In parallel, circadian clock neurons remodel their neurites, growing and shrinking across the day to shape circadian behavior. Remarkably, this neuronal remodeling relies on a cycle of temporally offset sphingolipid biosynthesis and catabolism. Thus, dynamic sphingolipid regulation by glia enables diurnal circuit remodeling and proper circadian behavior.