Summary: A protein called Scribble appears to orchestrate the intracellular signaling process for forgetting, a new study reports.
Source: Scripps Research Institute.
When Elvis released his first number-one country hit “I Forgot to Remember to Forget” in 1955, the song was more correct scientifically than he could have imagined. Humans need to forget as part of the brain’s system for the management of memories acquired across a lifetime.
“Understanding the process of forgetting could have an enormous impact on how we treat a whole range of diseases,” said Ron Davis, chair of the Department of Neuroscience on the Florida campus of The Scripps Research Institute (TSRI). “Certain memories are intrusive and, with sufficient knowledge of how the brain forgets, we should be able to remove selective memories. Alternatively, we could find a way to inhibit forgetting in those suffering from memory disorders such as Alzheimer’s disease.”
The new study, published June 2, 2016 online ahead of print by the journal Neuron, uncovers a new aspect of how this process works. The results show that a protein called “Scribble” orchestrates the intracellular signaling processes for forgetting, joining several molecules to forge a pathway.
To conduct this research, Davis and his colleagues turned to Drosophila, or the common fruit fly, a critical model for studying memory found to be highly applicable to humans.
By “knocking down” the expression of the gene that produces Scribble, the researchers produced flies that were able to remember twice as much as normal flies, simply because they failed to forget at the normal rate. The researchers also identified Scribble’s crucial role in interacting with other key molecular players for forgetting within the fly brain.
“What Scribble does is combine the Rac1 and dopamine pathways together into a single dynamic pathway that controls active forgetting,” Davis said. “It orchestrates a series of molecules that are involved in this particular forgetting pathway, and there may well be others we have yet to discover.”
“The Scribble protein is expressed in the same neurons that encode olfactory memories,” said TSRI Senior Staff Scientist Isaac Cervantes-Sandoval, the study’s first author. “We were able to show that it regulates memory by involvement in this particular forgetting pathway, an important biological process that has been surprisingly ignored.”
In addition to Davis and Cervantes-Sandoval, other authors of the study, “Scribble Scaffolds a Signalosome for Active Forgetting,” are Molee Chakraborty and Courtney MacMullen of TSRI.
Funding: This work was supported by the National Institutes of Health (grants 2R37NS19904 and 2R01NS05235).
Source: Scripps Research Institute
Image Source: This NeuroscienceNews.com image is in the public domain.
Original Research Abstract “Scribble Scaffolds a Signalosome for Active Forgetting” by Isaac Cervantes-Sandoval, Molee Chakraborty, Courtney MacMullen, and Ronald L. Davis in Neuron. Published online June 2 2016 doi:10.1016/j.neuron.2016.05.010
Scribble Scaffolds a Signalosome for Active Forgetting
•Scribble is a Drosophila memory suppressor gene
•The gene is expressed and functions in mushroom body and dopaminergic neurons
•It is necessary for normal active forgetting
•It regulates memory loss by scaffolding a forgetting signalosome
Forgetting, one part of the brain’s memory management system, provides balance to the encoding and consolidation of new information by removing unused or unwanted memories or by suppressing their expression. Recent studies identified the small G protein, Rac1, as a key player in the Drosophila mushroom bodies neurons (MBn) for active forgetting. We subsequently discovered that a few dopaminergic neurons (DAn) that innervate the MBn mediate forgetting. Here we show that Scribble, a scaffolding protein known primarily for its role as a cell polarity determinant, orchestrates the intracellular signaling for normal forgetting. Knocking down scribble expression in either MBn or DAn impairs normal memory loss. Scribble interacts physically and genetically with Rac1, Pak3, and Cofilin within MBn, nucleating a forgetting signalosome that is downstream of dopaminergic inputs that regulate forgetting. These results bind disparate molecular players in active forgetting into a single signaling pathway: Dopamine→ Dopamine Receptor→ Scribble→ Rac→ Cofilin.
“Scribble Scaffolds a Signalosome for Active Forgetting” by Isaac Cervantes-Sandoval, Molee Chakraborty, Courtney MacMullen, and Ronald L. Davis in Neuron. Published online June 2 2016 doi:10.1016/j.neuron.2016.05.010