Drosophila CPEB, Orb2, a Putative Biochemical Engram of Long-term Memory

Abstract

How a transient experience creates an enduring yet dynamic memory remains a fundamental unresolved issue in studies of memory. Experience-dependent aggregation of the RNA-binding protein CPEB/Orb2 is one of the candidate mechanisms of memory maintenance. Here, using tools that allow rapid and reversible inactivation of Orb2 protein I find that Orb2 activity is required for encoding and recall of memory. Blocking the Orb2 oligomerization process by interfering with the protein phosphorylation pathway or expressing an anti-amyloidogenic peptide impairs long-term memory. Facilitating Orb2 aggregation by a DNA-J family chaperone, JJJ2, enhances the animal’s capacity to form long-term memory. Finally, I have developed tools to visualize training-dependent aggregation of Orb2. I find that aggregated Orb2 in subset of mushroom body neurons can serve as a “molecular signature” of memory and predict memory strength. My data indicate that self-sustaining aggregates of Orb2 may serve as a physical substrate of memory and provide a molecular basis for the perduring yet malleable nature of memory.